2,031 results on '"DEOXYCYTIDINE"'
Search Results
2. The Role of Different TET Proteins in Cytosine Demethylation Revealed by Mathematical Modeling.
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Kurasz, Karolina, Rzeszowska-Wolny, Joanna, Oliński, Ryszard, Foksiński, Marek, and Fujarewicz, Krzysztof
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DEMETHYLATION ,MATHEMATICAL models ,PROTEINS ,CYTOSINE ,DEOXYCYTIDINE ,CELL lines - Abstract
In living cells, some reactions can be conducted by more than one enzyme and sometimes it is difficult to establish which enzyme is responsible. Such is the case with proteins from the TET family, capable of converting 5-methyl-2'-deoxycytidine (5- m d C ) in DNA to 5-(hydroxymethyl)-2'-deoxycytidine (5- h m d C ) and further to 5-formyl-2'-deoxycytidine (5- f d C ) and 5-carboxy-2'-deoxycytidine (5- c a d C ). The estimation of the efficiency of particular TETs in particular oxidative reactions and different cell types is important but experimentally difficult. Here, we propose an approach with mathematical modeling in which methylation and known deoxycytidine modification pathways are presented by 343 possible model versions with assumed different combinations of TET1, 2, and 3 activities in different pathways. Model parameters were calculated on the basis of 5- m d C , 5- h m d C , 5- f d C , 5- c a d C , and 5- h m d U levels experimentally assessed in five human cultured cell lines and previously published. Selection of the model versions that give in simulations the best average fit to experimental data suggested that not all TET proteins participate in all modification reactions and that TET3 activity may be especially important in the reaction of 5- f d C removal. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Protein engineering a PhotoRNR chimera based on a unifying evolutionary apparatus among the natural classes of ribonucleotide reductases.
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Song, David Y., Stubbe, JoAnne, and Nocera, Daniel G.
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REDUCTASES , *PROTEIN engineering , *ADENOSINE triphosphate , *RADICALS (Chemistry) , *DEOXYCYTIDINE - Abstract
Ribonucleotide reductases (RNRs) are essential enzymes that catalyze the de novo transformation of nucleoside 5- di(tri)phosphates [ND(T)Ps, where N is A, U, C, or G] to their corresponding deoxynucleotides. Despite the diversity of factors required for function and the low sequence conservation across RNRs, a unifying apparatus consolidating RNR activity is explored. We combine aspects of the protein subunit simplicity of class II RNR with a modified version of Escherichia coli class la photoRNRs that initiate radical chemistry with light to engineer a mimic of a class II enzyme. The design of this RNR involves fusing a truncated form of the active site containing α subunit with the functionally important C- terminal tail of the radical- generating β subunit to render a chimeric RNR. Inspired by a recent cryo- EM structure, a [Re] photooxidant is located adjacent to Y356[β], which is an essential component of the radical transport pathway in class I RNRs. Combination of this RNR photochimera with cytidine diphosphate (CDP), adenosine triphosphate (ATP), and light resulted in the generation of Y356• along with production of deoxycytidine diphosphate (dCDP) and cytosine. The photoproducts reflect an active site chemistry consistent with both the consensus mechanism of RNR and chemistry observed when RNR is inactivated by mechanism- based inhibitors in the active site. The enzymatic activity of the RNR photochimera in the absence of any β metallocofactor highlights the adaptability of the 10- stranded αβ barrel finger loop to support deoxynucleotide formation and accommodate the design of engineered RNRs. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Development of an artificial intelligence-derived histologic signature associated with adjuvant gemcitabine treatment outcomes in pancreatic cancer.
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Nimgaonkar, Vivek, Krishna, Viswesh, Krishna, Vrishab, Tiu, Ekin, Joshi, Anirudh, Vrabac, Damir, Bhambhvani, Hriday, Smith, Katelyn, Johansen, Julia S, Makawita, Shalini, Musher, Benjamin, Mehta, Arnav, Hendifar, Andrew, Wainberg, Zev, Sohal, Davendra, Fountzilas, Christos, Singhi, Aatur, Rajpurkar, Pranav, and Collisson, Eric A
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Humans ,Carcinoma ,Pancreatic Ductal ,Pancreatic Neoplasms ,Deoxycytidine ,Treatment Outcome ,Artificial Intelligence ,Biomarkers ,Gemcitabine ,digital pathology ,pancreatic cancer ,predictive biomarker ,Rare Diseases ,Orphan Drug ,Digestive Diseases ,Pancreatic Cancer ,Cancer ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Good Health and Well Being - Abstract
Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.
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- 2023
5. Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trialResearch in context
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Heather Pekeles, Saoussen Berrahmoune, Christelle Dassi, Anthony C.T. Cheung, Tommy Gagnon, Paula J. Waters, Ralf Eberhard, Daniela Buhas, and Kenneth A. Myers
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POLG ,Deoxynucleosides ,Deoxycytidine ,Deoxythymidine ,Thymidine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months–12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders. Methods: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023. Findings: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5–∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12–∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved. Interpretation: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders. Funding: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.
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- 2024
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6. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
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Winstel, Volker, Abt, Evan R., Le, Thuc M., and Radu, Caius G.
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DEOXYCYTIDINE , *STAPHYLOCOCCUS aureus , *ABSCESSES , *PATHOGENIC microorganisms , *DEOXYRIBONUCLEOSIDES , *MICROBIAL growth - Abstract
Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI- 87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI- 87- mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Unmasking the Metabolite Signature of Bladder Cancer: A Systematic Review.
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Pereira, Francisca, Domingues, M. Rosário, Vitorino, Rui, Guerra, Inês M. S., Santos, Lúcio Lara, Ferreira, José Alexandre, and Ferreira, Rita
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BLADDER cancer , *PANTOTHENIC acid , *MASS spectrometry , *DEOXYCYTIDINE , *CELL culture , *MICROBIAL metabolites - Abstract
Bladder cancer (BCa) research relying on Omics approaches has increased over the last few decades, improving the understanding of BCa pathology and contributing to a better molecular classification of BCa subtypes. To gain further insight into the molecular profile underlying the development of BCa, a systematic literature search was performed in PubMed until November 2023, following the PRISMA guidelines. This search enabled the identification of 25 experimental studies using mass spectrometry or nuclear magnetic resonance-based approaches to characterize the metabolite signature associated with BCa. A total of 1562 metabolites were identified to be altered by BCa in different types of samples. Urine samples displayed a higher likelihood of containing metabolites that are also present in bladder tumor tissue and cell line cultures. The data from these comparisons suggest that increased concentrations of L-isoleucine, L-carnitine, oleamide, palmitamide, arachidonic acid and glycoursodeoxycholic acid and decreased content of deoxycytidine, 5-aminolevulinic acid and pantothenic acid should be considered components of a BCa metabolome signature. Overall, molecular profiling of biological samples by metabolomics is a promising approach to identifying potential biomarkers for early diagnosis of different BCa subtypes. However, future studies are needed to understand its biological significance in the context of BCa and to validate its clinical application. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Dynamic Behavior and Ligand Binding Properties of the Wild Type Deoxycytidine Kinase and its Characterized Gemcitabine-Resistant Variant: A Bioinformatics and Computational Study.
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Rahmati, Yasmin, Khalifeh, Khosrow, and Heshmati, Emran
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DEOXYCYTIDINE , *MULTIENZYME complexes , *STANDARD deviations , *GENETIC mutation , *MOLECULAR dynamics , *LIGAND binding (Biochemistry) - Abstract
The main challenge in using gemcitabine, a nucleoside analogue anti-cancer, includes resistance of some patients to this compound due to the genetic mutations on deoxycytidine kinase (dCK) that are found in a fraction of the human population. Here, we investigated the dynamics behavior and ligand binding properties of the wild type (WT) dCK and its characterized double mutant using a combination of bioinformatics tools and molecular dynamics (MD) simulation studies. Root-mean-square deviation (RMSD) values of the WT and mutant enzyme in complex with both ligands (deoxycytidine/gemcitabine) demonstrated that the WT enzyme forms a more stable complex with gemcitabine, as compared with its natural ligand (deoxycytidine). However, the stability of the double mutant-deoxycytidine complex is greater, when compared with gemcitabine. It was also found that Arg131 as a critical residue can affect the binding pattern of the enzyme to ligands in a manner that the WT enzyme can interact with both ligands, while, the mutant enzyme cannot establish efficient interaction with gemcitabine, and shows high affinity to deoxycytidine. These data together indicate that gemcitabine can interact with the WT enzyme in a competitive manner, while double mutant can be considered as a resistant variant against gemcitabine. The interaction of anti-cancer gemcitabine with deoxycytidine kinase (dCK) was compared with its natural analogue; deoxycytidine. The dynamics behavior of the representative drug-resistant mutant of deoxycytidine kinase (dCK) was investigated in comparison with the wild type enzyme. The results of this study explain the mechanism of resistance of resistant variant against gemcitabine. [ABSTRACT FROM AUTHOR]
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- 2024
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9. A phase I dose escalation, dose expansion and pharmacokinetic trial of gemcitabine and alisertib in advanced solid tumors and pancreatic cancer
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Chen, Justin A, Huynh, Jasmine C, Wu, Chun-Yi, Yu, Ai-Ming, Matsukuma, Karen, Semrad, Thomas J, Gandara, David R, Li, Tianhong, Riess, Jonathan W, Tam, Kit, Mack, Philip C, Martinez, Anthony, Mahaffey, Nichole, Kelly, Karen L, and Kim, Edward J
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Digestive Diseases ,Orphan Drug ,Cancer ,Pancreatic Cancer ,Patient Safety ,Clinical Research ,Rare Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adenocarcinoma ,Antineoplastic Combined Chemotherapy Protocols ,Azepines ,Deoxycytidine ,Humans ,Maximum Tolerated Dose ,Neoplasms ,Pancreatic Neoplasms ,Pyrimidines ,Gemcitabine ,Alisertib ,Pharmacokinetics ,Aurora kinase a ,Phase I ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
PurposeAurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.MethodsKey inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles.ResultsIn total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.ConclusionsThis trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.
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- 2022
10. Study of protonated dimers of cytosine, cytidine, and deoxycytidine using survival yield method and quantum mechanics calculations.
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Jankowski, Wojciech, Hoffmann, Marcin, Półrul, Paulina, and Frańska, Magdalena
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QUANTUM mechanics , *CYTOSINE , *DEOXYCYTIDINE , *DIMERS , *DENSITY functional theory , *IONS spectra - Abstract
Rationale: Cytosine and its conjugates are prone to form protonated, triply‐bonded dimers. Therefore, the nucleic‐acid cytosine‐rich sequence forms the four‐stranded noncanonical secondary structure known as the intercalated motif (i‐motif). This process has resulted in studies on cytosine protonated dimers. This communication focuses on the protonated dimers of cytosine and its nucleoside using the survival yield (SY) method and quantum mechanics calculations. Methods: To obtain the precursor ion fragmentation curve, the plot of SY against Ecomδ, the product ion spectra of the protonated dimers were obtained using a Waters/Micromass Q‐TOF Premier mass spectrometer. Quantum mechanics calculations were performed using GAUSSIAN 16, and full geometry optimizations and energy calculations were performed within the density functional theory framework at B3LYP/6‐31G(d,p). Results: The precursor ion fragmentation curve allowed the rating of the gas‐phase stabilities of the analyzed protonated dimers. Substitution of sugar moiety at N1 cytosine atom decreased the gas‐phase stabilities of the protonated dimers. The deoxycytidine dimer was found to be more stable than the cytidine dimer and cytidine–deoxycytidine dimer. Quantum chemical calculations indicated that cytosine aminohydroxy tautomer may be involved in the formation of protonated cytosine–cytosine nucleoside dimers but not in the formation of cytosine dimers. Conclusions: The results obtained for nucleoside dimers indicated that the SY method may reflect the i‐motif stabilities observed under physiological conditions. Therefore, the analysis of other protonated dimers of variously substituted cytosine–cytosine nucleoside using the SY method may be important to study the effect of cytosine substitution on the i‐motif stabilities. Cytosine tautomer containing C2‐OH... N(2H)‐C4 moiety may be involved in the formation of protonated cytosine–cytosine nucleoside dimers. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Self-digestive solution of Lysobacter enzymogenes LE16 as a biofungicide to control plant powdery mildew.
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Chen, Danmei, Li, Zhimo, Huang, Chunyang, and Yang, Hongjun
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POWDERY mildew diseases , *CUCUMBERS , *PLANT diseases , *IRON , *FIELD research , *DEOXYCYTIDINE , *ECHINOCANDINS - Abstract
The self-digestive solution (SDS) of the biocontrol bacterium Lysobacter enzymogenes LE16 shows strong antagonistic activities against multiple soil-borne phytopathogens but the positive evidence of this bacterium against plant foliar disease is still scanty. Thus, laboratory, greenhouse, and field experiments were carried out to estimate the efficacies of SDS, S-SDS (stored at room temperature for 12 months), and H-SDS (heated at 100°C for 30 min) against plant powdery mildew. This bacterium produced hydrolases (phosphatase, protease, lysozyme, chitinase, and β-1,3-glucanase) that degrade pathogen cell components and siderophores that compete for iron with phytopathogens. The top five antimicrobial metabolites identified in SDS were pyroglutamic acid, deoxycytidine, pyrrole-2-carboxylic acid, 13-oxo-9,11-tridecadienoic acid, and 3'-amino-3'-deoxythimidine. Among them, pyroglutamic acid may play a vital role in powdery mildew control. As a result, SDS, S-SDS, and H-SDS strongly inhibited the conidial germination of Erysiphe cichoracearum and Sphaerotheca fuliginea. The application of SDS significantly increased the activity of antioxidant enzymes in crop leaves and effectively controlled tobacco and cucumber powdery mildew in the greenhouse and the field. Therefore, L. enzymogenes LE16 can effectively control powdery mildew. The underlying mechanisms may be attributed to the induction of plant systemic resistance and the production of antifungal substances. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Functional Prokaryotic-Like Deoxycytidine Triphosphate Deaminases and Thymidylate Synthase in Eukaryotic Social Amoebae: Vertical, Endosymbiotic, or Horizontal Gene Transfer?
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Liang, Heng, Mower, Jeffrey P, and Chia, Catherine P
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HORIZONTAL gene transfer ,THYMIDYLATE synthase ,DEOXYCYTIDINE ,DEAMINASES ,GENETIC transformation ,PROTEOBACTERIA ,EUKARYOTES - Abstract
The de novo synthesis of deoxythymidine triphosphate uses several pathways: gram-negative bacteria use deoxycytidine triphosphate deaminase to convert deoxycytidine triphosphate into deoxyuridine triphosphate, whereas eukaryotes and gram-positive bacteria instead use deoxycytidine monophosphate deaminase to transform deoxycytidine monophosphate to deoxyuridine monophosphate. It is then unusual that in addition to deoxycytidine monophosphate deaminases, the eukaryote Dictyostelium discoideum has 2 deoxycytidine triphosphate deaminases (Dcd1
Dicty and Dcd2Dicty ). Expression of either DcdDicty can fully rescue the slow growth of an Escherichia coli dcd knockout. Both DcdDicty mitigate the hydroxyurea sensitivity of a Schizosaccharomyces pombe deoxycytidine monophosphate deaminase knockout. Phylogenies show that Dcd1Dicty homologs may have entered the common ancestor of the eukaryotic groups of Amoebozoa, Obazoa, Metamonada, and Discoba through an ancient horizontal gene transfer from a prokaryote or an ancient endosymbiotic gene transfer from a mitochondrion, followed by horizontal gene transfer from Amoebozoa to several other unrelated groups of eukaryotes. In contrast, the Dcd2Dicty homologs were a separate horizontal gene transfer from a prokaryote or a virus into either Amoebozoa or Rhizaria, followed by a horizontal gene transfer between them. ThyXDicty , the D. discoideum thymidylate synthase, another enzyme of the deoxythymidine triphosphate biosynthesis pathway, was suggested previously to be acquired from the ancestral mitochondria or by horizontal gene transfer from alpha-proteobacteria. ThyXDicty can fully rescue the E. coli thymidylate synthase knockout, and we establish that it was obtained by the common ancestor of social amoebae not from mitochondria but from a bacterium. We propose horizontal gene transfer and endosymbiotic gene transfer contributed to the enzyme diversity of the deoxythymidine triphosphate synthesis pathway in most social amoebae, many Amoebozoa, and other eukaryotes. [ABSTRACT FROM AUTHOR]- Published
- 2023
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13. A new technique for the analysis of metabolic pathways of cytidine analogues and cytidine deaminase activities in cells.
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Ligasová, Anna, Piskláková, Barbora, Friedecký, David, and Koberna, Karel
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CYTIDINE deaminase , *DEOXYCYTIDINE , *DNA replication , *CYTOTOXINS , *CELL lines - Abstract
Deoxycytidine analogues (dCas) are widely used for the treatment of malignant diseases. They are commonly inactivated by cytidine deaminase (CDD), or by deoxycytidine monophosphate deaminase (dCMP deaminase). Additional metabolic pathways, such as phosphorylation, can substantially contribute to their (in)activation. Here, a new technique for the analysis of these pathways in cells is described. It is based on the use of 5-ethynyl 2′-deoxycytidine (EdC) and its conversion to 5-ethynyl 2′-deoxyuridine (EdU). Its use was tested for the estimation of the role of CDD and dCMP deaminase in five cancer and four non-cancer cell lines. The technique provides the possibility to address the aggregated impact of cytidine transporters, CDD, dCMP deaminase, and deoxycytidine kinase on EdC metabolism. Using this technique, we developed a quick and cheap method for the identification of cell lines exhibiting a lack of CDD activity. The data showed that in contrast to the cancer cells, all the non-cancer cells used in the study exhibited low, if any, CDD content and their cytidine deaminase activity can be exclusively attributed to dCMP deaminase. The technique also confirmed the importance of deoxycytidine kinase for dCas metabolism and indicated that dCMP deaminase can be fundamental in dCas deamination as well as CDD. Moreover, the described technique provides the possibility to perform the simultaneous testing of cytotoxicity and DNA replication activity. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years.
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Huschner, Franz, Głowacka-Walas, Jagoda, Mills, James D., Klonowska, Katarzyna, Lasseter, Kathryn, Asara, John M., Moavero, Romina, Hertzberg, Christoph, Weschke, Bernhard, Riney, Kate, Feucht, Martha, Scholl, Theresa, Krsek, Pavel, Nabbout, Rima, Jansen, Anna C., Petrák, Bořivoj, van Scheppingen, Jackelien, Zamecnik, Josef, Iyer, Anand, and Anink, Jasper J.
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TUBEROUS sclerosis ,BLOOD testing ,INFANTS ,BLOOD proteins ,DEOXYCYTIDINE - Abstract
We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC. A comprehensive multi-omic analysis of the EPISTOP trial for Tuberous Sclerosis Complex (TSC). was performed. Here, authors show many differences in serum proteins and metabolites, and blood RNA species, including associations with seizure development. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Quantitative LC–MS study of compounds found predictive of COVID-19 severity and outcome.
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Roberts, Ivayla, Wright Muelas, Marina, Taylor, Joseph M., Davison, Andrew S., Winder, Catherine L., Goodacre, Royston, and Kell, Douglas B.
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COVID-19 pandemic , *COVID-19 , *QUANTITATIVE research , *TRYPTOPHAN , *KYNURENINE , *DEOXYCYTIDINE - Abstract
Introduction: Since the beginning of the SARS-CoV-2 pandemic in December 2019 multiple metabolomics studies have proposed predictive biomarkers of infection severity and outcome. Whilst some trends have emerged, the findings remain intangible and uninformative when it comes to new patients. Objectives: In this study, we accurately quantitate a subset of compounds in patient serum that were found predictive of severity and outcome. Methods: A targeted LC–MS method was used in 46 control and 95 acute COVID-19 patient samples to quantitate the selected metabolites. These compounds included tryptophan and its degradation products kynurenine and kynurenic acid (reflective of immune response), butyrylcarnitine and its isomer (reflective of energy metabolism) and finally 3′,4′-didehydro-3′-deoxycytidine, a deoxycytidine analogue, (reflective of host viral defence response). We subsequently examine changes in those markers by disease severity and outcome relative to those of control patients' levels. Results & conclusion: Finally, we demonstrate the added value of the kynurenic acid/tryptophan ratio for severity and outcome prediction and highlight the viral detection potential of ddhC. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Vedolizumab as Rescue Therapy in Carboplatin-Gemcitabine-Induced Triggered Acute Severe Ulcerative Colitis Flare-Up.
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Pellegrino, Raffaele, Fasano, Morena, Morgillo, Floriana, Palladino, Giovanna, Vassallo, Isabella, Pirozzi, Mario, Imperio, Giuseppe, Auletta, Salvatore, Ventura, Andrea, Panarese, Iacopo, Federico, Alessandro, and Gravina, Antonietta Gerarda
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THERAPEUTIC use of monoclonal antibodies ,ULCERATIVE colitis ,CARBOPLATIN ,DEOXYCYTIDINE ,MONOCLONAL antibodies ,GEMCITABINE ,SEVERITY of illness index ,TREATMENT effectiveness ,SALVAGE therapy - Abstract
Approximately 20% of patients with ulcerative colitis (UC) develop acute severe UC (ASUC), for which intravenous systemic steroid therapy and possibly infliximab-based rescue therapy are generally imposed. However, there are no significant guideline recommendations on ASUC regarding vedolizumab as an alternative in this setting. A case report was presented where a patient with steroid-dependent UC developed ASUC induced by second-line chemotherapy. Treatment with intravenous methylprednisolone was imposed, but there was no reduction in bowel movements in the days following admission. Rescue therapy with infliximab was contraindicated because of the oncologic history. Surgical consultation, contraindicated colectomy, and administration of vedolizumab 300 mg were initiated. After infusion with vedolizumab, there was a significant reduction in bowel movements starting the day after infusion until normalisation of bowel movements within three days and the concomitant normalisation of inflammatory indices. The patient is currently in clinical remission, on therapy with vedolizumab 108 mg subcutaneously every two weeks, and is in oncologic follow-up for pulmonary neoplasm. This case highlights the novel potential of vedolizumab as a possible rescue therapy in ASUC, especially in special populations, where it may offer a better safety profile. Although cyclosporine and infliximab still represent the mainstays of salvage therapy for steroid-refractory ASUC, new therapeutic agents may also be effective, such as vedolizumab, ustekinumab, and anti-Janus kinase agents. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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17. Comparative effectiveness of neoadjuvant chemotherapy in bladder and upper urinary tract urothelial carcinoma.
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DAndrea, David, Matin, Surena, Black, Peter, Petros, Firas, Zargar, Homayoun, Dinney, Colin, Cookson, Michael, Kassouf, Wassim, DallEra, Marc, McGrath, John, Wright, Jonathan, Thorpe, Andrew, Morgan, Todd, Holzbeierlein, Jeffrey, Bivalacqua, Trinity, Sridhar, Srikala, North, Scott, Barocas, Daniel, Lotan, Yair, Stephenson, Andrew, van Rhijn, Bas, Spiess, Philippe, Daneshmand, Siamak, and Shariat, Shahrokh
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#BladderCancer ,#blcsm ,#uroonc ,#utuc ,bladder cancer ,neoadjuvant chemotherapy ,response ,survival ,upper tract urothelial carcinoma ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Transitional Cell ,Cisplatin ,Comparative Effectiveness Research ,Cystectomy ,Deoxycytidine ,Doxorubicin ,Female ,Humans ,Kidney Neoplasms ,Male ,Methotrexate ,Middle Aged ,Neoadjuvant Therapy ,Neoplasm Staging ,Nephroureterectomy ,Proportional Hazards Models ,Retrospective Studies ,Survival Rate ,Treatment Outcome ,Ureteral Neoplasms ,Urinary Bladder Neoplasms ,Vinblastine ,Gemcitabine - Abstract
OBJECTIVE: To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery. PATIENTS AND METHODS: Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses. RESULTS: A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P
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- 2021
18. Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice
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Peran, Ivana, Dakshanamurthy, Sivanesan, McCoy, Matthew D, Mavropoulos, Anastasia, Allo, Bedilu, Sebastian, Aimy, Hum, Nicholas R, Sprague, Sara C, Martin, Kelly A, Pishvaian, Michael J, Vietsch, Eveline E, Wellstein, Anton, Atkins, Michael B, Weiner, Louis M, Quong, Andrew A, Loots, Gabriela G, Yoo, Stephen S, Assefnia, Shahin, and Byers, Stephen W
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Pancreatic Cancer ,Digestive Diseases ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Cadherins ,Cancer-Associated Fibroblasts ,Carcinoma ,Pancreatic Ductal ,Deoxycytidine ,Disease Models ,Animal ,Disease Progression ,Drug Resistance ,Neoplasm ,Extracellular Matrix ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Metallothionein 3 ,Mice ,Mice ,Knockout ,Pancreas ,Pancreatic Neoplasms ,Pancreaticoduodenectomy ,Tumor Escape ,Tumor Microenvironment ,Gemcitabine ,Immunomodulation ,Anti-Tumor Immunity ,Activated Stroma ,Desmoplasia ,Inflammation ,Clinical Sciences ,Neurosciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
Background & aimsPancreatic ductal adenocarcinomas (PDACs) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). We investigated strategies to disrupt interactions among CAFs, the immune system, and cancer cells, focusing on adhesion molecule CDH11, which has been associated with other fibrotic disorders and is expressed by activated fibroblasts.MethodsWe compared levels of CDH11 messenger RNA in human pancreatitis and pancreatic cancer tissues and cells with normal pancreas, and measured levels of CDH11 protein in human and mouse pancreatic lesions and normal tissues. We crossed p48-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ (KPC) mice with CDH11-knockout mice and measured survival times of offspring. Pancreata were collected and analyzed by histology, immunohistochemistry, and (single-cell) RNA sequencing; RNA and proteins were identified by imaging mass cytometry. Some mice were given injections of PD1 antibody or gemcitabine and survival was monitored. Pancreatic cancer cells from KPC mice were subcutaneously injected into Cdh11+/+ and Cdh11-/- mice and tumor growth was monitored. Pancreatic cancer cells (mT3) from KPC mice (C57BL/6), were subcutaneously injected into Cdh11+/+ (C57BL/6J) mice and mice were given injections of antibody against CDH11, gemcitabine, or small molecule inhibitor of CDH11 (SD133) and tumor growth was monitored.ResultsLevels of CDH11 messenger RNA and protein were significantly higher in CAFs than in pancreatic cancer epithelial cells, human or mouse pancreatic cancer cell lines, or immune cells. KPC/Cdh11+/- and KPC/Cdh11-/- mice survived significantly longer than KPC/Cdh11+/+ mice. Markers of stromal activation entirely surrounded pancreatic intraepithelial neoplasias in KPC/Cdh11+/+ mice and incompletely in KPC/Cdh11+/- and KPC/Cdh11-/- mice, whose lesions also contained fewer FOXP3+ cells in the tumor center. Compared with pancreatic tumors in KPC/Cdh11+/+ mice, tumors of KPC/Cdh11+/- mice had increased markers of antigen processing and presentation; more lymphocytes and associated cytokines; decreased extracellular matrix components; and reductions in markers and cytokines associated with immunosuppression. Administration of the PD1 antibody did not prolong survival of KPC mice with 0, 1, or 2 alleles of Cdh11. Gemcitabine extended survival of KPC/Cdh11+/- and KPC/Cdh11-/- mice only or reduced subcutaneous tumor growth in mT3 engrafted Cdh11+/+ mice when given in combination with the CDH11 antibody. A small molecule inhibitor of CDH11 reduced growth of pre-established mT3 subcutaneous tumors only if T and B cells were present in mice.ConclusionsKnockout or inhibition of CDH11, which is expressed by CAFs in the pancreatic tumor stroma, reduces growth of pancreatic tumors, increases their response to gemcitabine, and significantly extends survival of mice. CDH11 promotes immunosuppression and extracellular matrix deposition, and might be developed as a therapeutic target for pancreatic cancer.
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- 2021
19. Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer
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Walsh, Christine S, Kamrava, Mitchell, Rogatko, Andre, Kim, Sungjin, Li, Andrew, Cass, Ilana, Karlan, Beth, and Rimel, Bobbie J
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Ovarian Cancer ,Rare Diseases ,Cancer ,Orphan Drug ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,B7-H1 Antigen ,CA-125 Antigen ,Cisplatin ,Deoxycytidine ,Drug Administration Schedule ,Drug Resistance ,Neoplasm ,Female ,Humans ,Middle Aged ,Neoplasm Recurrence ,Local ,Neoplasm Staging ,Ovarian Neoplasms ,Platinum ,Progression-Free Survival ,Survival Rate ,Treatment Outcome ,Gemcitabine ,General Science & Technology - Abstract
ObjectiveTo evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer.MethodsPatients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3-6 and as maintenance monotherapy in cycles 7-34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival.ResultsAn interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual.ConclusionsThe addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.
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- 2021
20. Meta-analysis examining overall survival in patients with pancreatic cancer treated with second-line 5-fluorouracil and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy: effect of performance status and comparison with other regimens
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Wainberg, Zev A, Feeney, Kynan, Lee, Myung Ah, Muñoz, Andrés, Gracián, Antonio Cubillo, Lonardi, Sara, Ryoo, Baek-Yeol, Hung, Annie, Lin, Yong, Bendell, Johanna, and Hecht, J Randolph
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Patient Safety ,Cancer ,Clinical Research ,Digestive Diseases ,Rare Diseases ,Pancreatic Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Antineoplastic Combined Chemotherapy Protocols ,Deoxycytidine ,Drug Resistance ,Neoplasm ,Drug-Related Side Effects and Adverse Reactions ,Fluorouracil ,Humans ,Karnofsky Performance Status ,Leucovorin ,Organoplatinum Compounds ,Oxaliplatin ,Pancreatic Neoplasms ,Prognosis ,Randomized Controlled Trials as Topic ,Risk Factors ,Survival Analysis ,Treatment Outcome ,Gemcitabine ,Pancreatic cancer ,Metastatic ,Performance status ,FOLFOX ,Meta-analysis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Epidemiology - Abstract
BackgroundPancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy.MethodsPubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients.ResultsOf 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX.ConclusionsBaseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.
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- 2020
21. Safety and Efficacy of Andecaliximab (GS‐5745) Plus Gemcitabine and Nab‐Paclitaxel in Patients with Advanced Pancreatic Adenocarcinoma: Results from a Phase I Study
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Bendell, Johanna, Sharma, Sunil, Patel, Manish R, Windsor, Kevin S, Wainberg, Zev A, Gordon, Michael, Chaves, Jorge, Berlin, Jordan, Brachmann, Carrie Baker, Zavodovskaya, Marianna, Liu, JieJane, Thai, Dung, Bhargava, Pankaj, Shah, Manish A, Khan, Saad A, and Starodub, Alexander
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Orphan Drug ,Digestive Diseases ,Patient Safety ,Clinical Trials and Supportive Activities ,Pancreatic Cancer ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Adenocarcinoma ,Albumins ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Deoxycytidine ,Humans ,Paclitaxel ,Pancreatic Neoplasms ,Treatment Outcome ,Tumor Microenvironment ,Gemcitabine ,Andecaliximab ,GS-5745 ,Matrix metalloproteinase 9 ,Pancreatic adenocarcinoma ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundMatrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma.Patients and methodsThis phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed.ResultsAndecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed.ConclusionAndecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma.Implications for practiceThe combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.
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- 2020
22. Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer
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Long, Qilai, Ma, Ai-Hong, Zhang, Hongyong, Cao, Zhixiu, Xia, Roger, Lin, Tzu-Yin, Sonpavde, Guru P, de Vere White, Ralph, Guo, Jianming, and Pan, Chong-Xian
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Urologic Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Proliferation ,Cell Survival ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Deoxycytidine ,Humans ,Mice ,Piperazines ,Programmed Cell Death 1 Receptor ,Protein Kinase Inhibitors ,Pyridines ,Urinary Bladder Neoplasms ,Xenograft Model Antitumor Assays ,Gemcitabine ,CDK4 ,6 ,Targeted therapy ,Chemotherapy ,Immunotherapy ,Bladder cancer ,Patient-derived xenograft ,CDK4/6 ,Oncology and carcinogenesis - Abstract
BackgroundPerturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy.ResultsOf the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models.ConclusionsThe CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.
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- 2020
23. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma
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Van Cutsem, Eric, Tempero, Margaret A, Sigal, Darren, Oh, Do-Youn, Fazio, Nicola, Macarulla, Teresa, Hitre, Erika, Hammel, Pascal, Hendifar, Andrew E, Bates, Susan E, Li, Chung-Pin, Hingorani, Sunil R, de la Fouchardiere, Christelle, Kasi, Anup, Heinemann, Volker, Maraveyas, Anthony, Bahary, Nathan, Layos, Laura, Sahai, Vaibhav, Zheng, Lei, Lacy, Jill, Park, Joon Oh, Portales, Fabienne, Oberstein, Paul, Wu, Wilson, Chondros, Dimitrios, and Bullock, Andrea J
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Clinical Research ,Rare Diseases ,Clinical Trials and Supportive Activities ,Pancreatic Cancer ,Digestive Diseases ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Aged ,Albumins ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Pancreatic Ductal ,Deoxycytidine ,Disease Progression ,Double-Blind Method ,Fatigue ,Female ,Humans ,Hyaluronic Acid ,Hyaluronoglucosaminidase ,Hyponatremia ,Male ,Middle Aged ,Paclitaxel ,Pancreatic Neoplasms ,Progression-Free Survival ,Response Evaluation Criteria in Solid Tumors ,Spasm ,Survival Rate ,HALO 109-301 Investigators ,Gemcitabine ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeTo evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA).Patients and methodsHALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1.ResultsAt data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%).ConclusionThe addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.
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- 2020
24. Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis
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Mancarella, Serena, Serino, Grazia, Dituri, Francesco, Cigliano, Antonio, Ribback, Silvia, Wang, Jingxiao, Chen, Xin, Calvisi, Diego F, and Giannelli, Gianluigi
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Liver Disease ,Biotechnology ,Rare Diseases ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adaptor Proteins ,Signal Transducing ,Amyloid Precursor Protein Secretases ,Animals ,Benzazepines ,Bile Duct Neoplasms ,Calcium-Binding Proteins ,Cell Line ,Tumor ,Cholangiocarcinoma ,Deoxycytidine ,Disease Progression ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Humans ,Matrix Metalloproteinase 13 ,Mice ,Nude ,Microvessels ,Neovascularization ,Pathologic ,RNA ,Messenger ,Receptor ,Notch1 ,Reproducibility of Results ,Signal Transduction ,Transcriptome ,Vascular Endothelial Growth Factor A ,Xenograft Model Antitumor Assays ,Gemcitabine ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. An altered expression and/or activation of NOTCH1-3 receptors has been shown to play a role in iCCA development and progression. In this study, we established a new CCA patient-derived xenograft model, which was validated by immunohistochemistry and transcriptomic analysis. The effects of Notch pathway suppression by the Crenigacestat (LY3039478)-specific inhibitor were evaluated in human iCCA cell lines and the PDX model. In vitro, LY3039478 significantly reduced Notch pathway components, including NICD1 and HES1, but not the other Notch receptors, in a panel of five different iCCA cell lines. In the PDX model, LY3039478 significantly inhibited the Notch pathway and tumor growth to the same extent as gemcitabine. Furthermore, gene expression analysis of iCCA mouse tissues treated with LY3039478 revealed a downregulation of VEGFA, HES1, and MMP13 genes. In the same tissues, DLL4 and CD31 co-localized, and their expression was significantly inhibited in the treated mice, as it happened in the case of MMP13. In an in vitro angiogenesis model, LY3039478 inhibited vessel formation, which was restored by the addition of MMP13. Finally, RNA-sequencing expression data of iCCA patients and matched surrounding normal liver tissues downloaded from the GEO database demonstrated that NOTCH1, HES1, MMP13, DLL4, and VEGFA genes were significantly upregulated in tumors compared with adjacent nontumorous tissues. These data were confirmed by our group, using an independent cohort of iCCA specimens. Conclusion: We have developed and validated a new iCCA PDX model to test in vivo the activity of LY3039478, demonstrating its inhibitory role in Notch-dependent angiogenesis. Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease.
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- 2020
25. Phase 1 Trial of Concurrent Gemcitabine and Cisplatin with Image Guided Intensity Modulated Radiation Therapy for Locoregionally Advanced Cervical Carcinoma
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Mell, Loren K, Xu, Ronghui, Yashar, Catheryn M, McHale, Michael T, Einck, John P, Mayadev, Jyoti, Lee, Euyhyun, Binder, Pratibha, Rash, Dominique, Eskander, Ramez, Heide, Elena S, Plaxe, Steven C, Mundt, Arno J, and Saenz, Cheryl C
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Cervical Cancer ,Clinical Trials and Supportive Activities ,Digestive Diseases ,Cancer ,6.5 Radiotherapy and other non-invasive therapies ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Cisplatin ,Combined Modality Therapy ,Deoxycytidine ,Female ,Humans ,Middle Aged ,Radiotherapy ,Image-Guided ,Radiotherapy ,Intensity-Modulated ,Treatment Outcome ,Uterine Cervical Neoplasms ,Young Adult ,Gemcitabine ,Other Physical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Theoretical and computational chemistry ,Medical and biological physics - Abstract
PurposeThe use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC.Methods and materialsWe conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%.ResultsBetween February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level.ConclusionsIG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing.
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- 2020
26. Phospho-valproic acid (MDC-1112) reduces pancreatic cancer growth in patient-derived tumor xenografts and KPC mice: enhanced efficacy when combined with gemcitabine
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Luo, Dingyuan, Digiovanni, Matthew G, Wei, Ran, Lacomb, Joseph F, Williams, Jennie L, Rigas, Basil, and Mackenzie, Gerardo G
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Digestive Diseases ,Pancreatic Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Abnormalities ,Multiple ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Line ,Tumor ,Cell Proliferation ,Deoxycytidine ,Disease Models ,Animal ,Humans ,Keratoconus ,Mice ,Organophosphates ,Pancreatic Neoplasms ,Signal Transduction ,Valproic Acid ,Xenograft Model Antitumor Assays ,Gemcitabine ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
New chemotherapeutic agents are needed for pancreatic cancer (PC). We have previously shown that phospho-valproic acid (MDC-1112) is effective in cell-line xenografts of PC. Here, we explored whether MDC-1112 is effective in additional clinically relevant animal models of PC and whether MDC-1112 enhances the anticancer effect of clinically used chemotherapeutic agents. MDC-1112 alone strongly reduced patient-derived pancreatic tumor xenograft growth, and extended survival of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mice. In both models, MDC-1112 inhibited STAT3 activation and its downstream signals, including Bcl-xL and cyclin D1. In human PC cell lines, P-V enhanced the growth inhibitory effect of gemcitabine (GEM), Abraxane and 5-FU, but not that of irinotecan. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of MDC-1112/GEM combination. Furthermore, MDC-1112 enhanced GEM's effect on colony formation, apoptosis, cell migration, and cell invasion. In vivo, MDC-1112 and GEM, given alone, reduced patient-derived pancreatic tumor xenograft growth by 58% and 87%, respectively; whereas MDC-1112/GEM combination reduced tumor growth by 94%, inducing tumor stasis. In conclusion, MDC-1112 should be further explored as a potential agent to be used in combination with GEM for treating PC.
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- 2020
27. Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers
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Mukhopadhyay, Suman, Goswami, Debanjan, Adiseshaiah, Pavan P, Burgan, William, Yi, Ming, Guerin, Theresa M, Kozlov, Serguei V, Nissley, Dwight V, and McCormick, Frank
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Pancreatic Cancer ,Digestive Diseases ,Cancer ,Rare Diseases ,Orphan Drug ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Antimetabolites ,Antineoplastic ,Carcinoma ,Pancreatic Ductal ,Cell Line ,Tumor ,Deoxycytidine ,Drug Resistance ,Neoplasm ,Glutaminase ,Glutamine ,Heterografts ,Humans ,Mice ,Mice ,Nude ,Mutation ,NF-E2-Related Factor 2 ,Neoplasm Proteins ,Pancreatic Neoplasms ,Prognosis ,Proto-Oncogene Proteins p21(ras) ,Random Allocation ,Tissue Array Analysis ,Up-Regulation ,Gemcitabine ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.
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- 2020
28. ATM-Mutated Pancreatic Cancer: Clinical and Molecular Response to Gemcitabine/Nab-Paclitaxel After Genome-Based Therapy Resistance.
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Martino, Candice, Pandya, Deep, Lee, Ronald, Levy, Gillian, Lo, Tammy, Lobo, Sandra, and Frank, Richard C
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Humans ,Pancreatic Neoplasms ,Paclitaxel ,Albumins ,Deoxycytidine ,Antineoplastic Combined Chemotherapy Protocols ,Treatment Outcome ,Drug Resistance ,Neoplasm ,Germ-Line Mutation ,Adult ,Female ,Ataxia Telangiectasia Mutated Proteins ,Gemcitabine ,Pancreatic Cancer ,Orphan Drug ,Cancer ,Rare Diseases ,Clinical Research ,Genetics ,Digestive Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,pancreatic cancer ,homologous recombination deficiency ,ATM mutation ,PARP inhibitor ,mutant KRAS ct DNA ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
Metastatic pancreatic cancer (PC) is an aggressive malignancy, with most patients deriving benefit only from first-line chemotherapy. Increasingly, the recommended treatment for those with a germline mutation in a gene involved in homologous recombination repair is with a platinum drug followed by a poly (ADP-ribose) polymerase (poly adenosine phosphate-ribose polymerase [PARP]) inhibitor. Yet, this is based largely on studies of BRCA1/2 or PALB2 mutated PC. We present the case of a 44-year-old woman with ATM-mutated PC who achieved stable disease as the best response to first-line fluorouracil, leucovorin, irinotecan, and oxaliplatin, followed by progression on a PARP inhibitor. In the setting of jaundice, painful hepatomegaly, and a declining performance status, she experienced rapid disease regression with the nonplatinum regimen, gemcitabine plus nab-paclitaxel. Both physical stigmata and abnormal laboratory values resolved, imaging studies showed a reduction in metastases and her performance status returned to normal. Measurement of circulating tumor DNA for KRAS G12R by digital droplet polymerase chain reaction confirmed a deep molecular response. This case highlights that first-line treatment with a platinum-containing regimen followed by PARP inhibition may not be the best choice for individuals with ATM-mutated pancreatic cancer. Additional predictors of treatment response are needed in this setting.
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- 2020
29. Phase 2 Trial of Neoadjuvant FOLFIRINOX and Intensity Modulated Radiation Therapy Concurrent With Fixed-Dose Rate-Gemcitabine in Patients With Borderline Resectable Pancreatic Cancer
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Tran, Nguyen H, Sahai, Vaibhav, Griffith, Kent A, Nathan, Hari, Kaza, Ravi, Cuneo, Kyle C, Shi, Jiaqi, Kim, Edward, Sonnenday, Christopher J, Cho, Clifford S, Lawrence, Theodore S, and Zalupski, Mark M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Pancreatic Cancer ,Clinical Research ,Vaccine Related ,Clinical Trials and Supportive Activities ,Patient Safety ,Rare Diseases ,Digestive Diseases ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.5 Radiotherapy and other non-invasive therapies ,6.1 Pharmaceuticals ,Adenocarcinoma ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,CA-19-9 Antigen ,Chemoradiotherapy ,Deoxycytidine ,Dose Fractionation ,Radiation ,Feasibility Studies ,Female ,Fluorouracil ,Humans ,Irinotecan ,Leucovorin ,Male ,Middle Aged ,Neoadjuvant Therapy ,Neutropenia ,Oxaliplatin ,Pancreatic Neoplasms ,Progression-Free Survival ,Radiotherapy ,Intensity-Modulated ,Gemcitabine ,Other Physical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Theoretical and computational chemistry ,Medical and biological physics - Abstract
PurposePreoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined.Methods and materialsPatients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m2 over 100 minutes) followed by 2 additional gemcitabine infusions. Computed tomography scans were performed at 2-month intervals during treatment. Patients without distant disease were offered surgical exploration. The primary objective was R0 resection rate with an alternate hypothesis of 55%. Secondary objectives included median progression-free survival (PFS), median overall survival (OS), response rate, and safety. The trial registration number is NCT01661088.ResultsTwenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached).ConclusionsNeoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable.
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- 2020
30. Eribulin Regresses a Doxorubicin-resistant Dedifferentiated Liposarcoma in a Patient-derived Orthotopic Xenograft Mouse Model
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IGARASHI, KENTARO, KAWAGUCHI, KEI, KIYUNA, TASUKU, MIYAKE, KENTARO, HIGUCHI, TAKASHI, YAMAMOTO, NORIO, HAYASHI, KATSUHIRO, KIMURA, HIROAKI, MIWA, SHINJI, SINGH, SHREE RAM, TSUCHIYA, HIROYUKI, and HOFFMAN, ROBERT M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Good Health and Well Being ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Dedifferentiation ,Cell Proliferation ,Deoxycytidine ,Docetaxel ,Doxorubicin ,Drug Resistance ,Neoplasm ,Furans ,Humans ,Indazoles ,Ketones ,Liposarcoma ,Male ,Mice ,Mice ,Nude ,Piperazines ,Pyridines ,Pyrimidines ,Sulfonamides ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,Gemcitabine ,Patient-derived orthotopic xenograft ,PDOX ,eribulin ,regression ,doxorubicin resistance ,dedifferentiated liposarcoma ,Immunology ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Background/aimDedifferentiated liposarcoma (DDLPS) is recalcitrant type of sarcoma. DDLPS has a low survival rate with high recurrence and metastasis. In the present study, we evaluated the efficacy of several drugs against doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model for precision oncology. To establish the PDOX model, a tumor from a patient who had recurrent high-grade DDLPS from the retroperitoneum was previously grown orthotopically in the retroperitoneum of nude mice.Materials and methodsWe randomized DDLPS PDOX models into 8 treatment groups when tumor volume became approximately 100 mm3: control, no treatment; G2, doxorubicin (DOX); G3, pazopanib (PAZ); G4, gemcitabine (GEM) combined with docetaxel (DOC); G5, trabectedin (YON); G6, temozolomide (TEM); G7, palbociclib (PAL); G8, eribulin (ERB). Tumor length and width were measured both at the beginning and at the end of treatment.ResultsAt the end of treatment (day 14), all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control, except DOX. ERB was significantly more effective and regressed tumor volume compared to other treatments on day 14 after initiation of treatment. No significant differences were found in the relative body weight on day 14 compared to day 0 in any group.ConclusionThe clinical potential of ERB against DDLPS is herein presented in a PDOX model.
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- 2020
31. Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis.
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Chen, Bao Ying, Salas, Jessica R., Trias, Alyssa O., Perez Rodriguez, Arely, Tsang, Jonathan E., Guemes, Miriam, Le, Thuc M., Galic, Zoran, Shepard, H. Michael, Steinman, Lawrence, Nathanson, David A., Czernin, Johannes, Witte, Owen N., Radu, Caius G., Schultz, Kenneth A., and Clark, Peter M.
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AUTOIMMUNE diseases , *DEOXYCYTIDINE , *MULTIPLE sclerosis , *LABORATORY mice , *T cells , *MYELIN oligodendrocyte glycoprotein , *CELL populations - Abstract
Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate‐limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35–55 and MOG1–125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE‐515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE‐515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE‐515 blocks activation‐induced B and T cell proliferation and MOG35–55‐specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35–55‐specific lymphocyte activation‐induced proliferation. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Tumor-specific delivery of gemcitabine with activatable liposomes
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Tucci, Samantha T, Kheirolomoom, Azadeh, Ingham, Elizabeth S, Mahakian, Lisa M, Tam, Sarah M, Foiret, Josquin, Hubbard, Neil E, Borowsky, Alexander D, Baikoghli, Mo, Cheng, R Holland, and Ferrara, Katherine W
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Pancreatic Cancer ,Digestive Diseases ,Rare Diseases ,Breast Cancer ,Women's Health ,Animals ,Antimetabolites ,Antineoplastic ,Breast Neoplasms ,Cell Line ,Tumor ,Delayed-Action Preparations ,Deoxycytidine ,Drug Delivery Systems ,Drug Liberation ,Female ,Humans ,Hyperthermia ,Induced ,Liposomes ,Mice ,Mice ,Inbred C57BL ,Pancreatic Neoplasms ,Temperature ,Gemcitabine ,Temperature-sensitive liposome ,Ultrasound ,Pancreatic ductal adenocarcinoma ,Breast cancer ,Biomedical Engineering ,Chemical Engineering ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences ,Biomedical engineering - Abstract
Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper (II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole%) then reached 12 wt% loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine‑copper mixture. The optimized gemcitabine liposomes released 60% and 80% of the gemcitabine within 1 and 5 min, respectively, at 42 °C. Liposomal encapsulation resulted in a circulation half-life of ~2 h in vivo (compared to reported circulation of 16 min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model of murine breast cancer with limited toxicity, enhancing survival when compared to treatment with gemcitabine alone. With 5% of the free gemcitabine dose (5 rather than 100 mg/kg), tumor growth was suppressed to the same degree as gemcitabine. Additionally, in a more aggressive tumor model of murine pancreatic cancer, liposomal gemcitabine combined with local hyperthermia induced cell death and regions of apoptosis and necrosis.
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- 2019
33. Epigallocatechin-3-Gallate (EGCG) Suppresses Pancreatic Cancer Cell Growth, Invasion, and Migration partly through the Inhibition of Akt Pathway and Epithelial-Mesenchymal Transition: Enhanced Efficacy when Combined with Gemcitabine.
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Wei, Ran, Penso, Natalia E Cortez, Hackman, Robert M, Wang, Yuefei, and Mackenzie, Gerardo G
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Cell Line ,Tumor ,Animals ,Mice ,Inbred C57BL ,Humans ,Pancreatic Neoplasms ,Neoplasm Invasiveness ,Catechin ,Deoxycytidine ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Burden ,Enzyme Stability ,Signal Transduction ,Cell Proliferation ,Cell Movement ,Proto-Oncogene Proteins c-akt ,Epithelial-Mesenchymal Transition ,Proteolysis ,Akt ,EMT ,epigallocatechin-3-gallate ,gemcitabine ,pancreatic cancer ,Cell Line ,Tumor ,Mice ,Inbred C57BL ,Food Sciences ,Nutrition and Dietetics - Abstract
Most pancreatic cancers are usually diagnosed at an advanced stage when they have already metastasized. Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, has been shown to reduce pancreatic cancer growth, but its effect on metastasis remains elusive. This study evaluated the capacity of EGCG to inhibit pancreatic cancer cell migration and invasion and the underlying mechanisms. EGCG reduced pancreatic cancer cell growth, migration, and invasion in vitro and in vivo. EGCG prevented "Cadherin switch" and decreased the expression level of TCF8/ZEB1, β-Catenin, and Vimentin. Mechanistically, EGCG inhibited the Akt pathway in a time-dependent manner, by suppressing IGFR phosphorylation and inducing Akt degradation. Co-treatment with catalase or N-Acetyl-L-cysteine did not abrogate EGCG's effect on the Akt pathway or cell growth. Moreover, EGCG synergized with gemcitabine to suppress pancreatic cancer cell growth, migration, and invasion, through modulating epithelial-mesenchymal transition markers and inhibiting Akt pathway. In summary, EGCG may prove beneficial to improve gemcitabine sensitivity in inhibiting pancreatic cancer cell migration and invasion, to some extent through the inhibition of Akt pathway and epithelial-mesenchymal transition.
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- 2019
34. Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.
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Wang, Man-Tzu, Fer, Nicole, Galeas, Jacqueline, Collisson, Eric A, Kim, Sung Eun, Sharib, Jeremy, and McCormick, Frank
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Carcinoma ,Pancreatic Ductal ,Pancreatic Neoplasms ,Adaptor Proteins ,Signal Transducing ,Phosphoproteins ,Transcription Factors ,RNA ,Small Interfering ,Deoxycytidine ,Antineoplastic Combined Chemotherapy Protocols ,Interleukin-6 ,Xenograft Model Antitumor Assays ,Signal Transduction ,Mutation ,Female ,Proto-Oncogene Proteins p21(ras) ,Leukemia Inhibitory Factor ,Gene Knockout Techniques ,Adaptor Proteins ,Signal Transducing ,Carcinoma ,Pancreatic Ductal ,Cell Line ,Tumor ,RNA ,Small Interfering - Abstract
KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.
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- 2019
35. Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma
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Ng, Kimmie, Hendifar, Andrew, Starodub, Alexander, Chaves, Jorge, Yang, Yingsi, Koh, Brian, Barbie, David, Hahn, William C, and Fuchs, Charles S
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Vaccine Related ,Clinical Research ,Orphan Drug ,Rare Diseases ,Pancreatic Cancer ,Cancer ,Clinical Trials and Supportive Activities ,Digestive Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Albumins ,Antineoplastic Combined Chemotherapy Protocols ,Benzamides ,Carcinoma ,Pancreatic Ductal ,Deoxycytidine ,Female ,Follow-Up Studies ,Humans ,Janus Kinase 1 ,Janus Kinase 2 ,Male ,Maximum Tolerated Dose ,Middle Aged ,Paclitaxel ,Pancreatic Neoplasms ,Prognosis ,Pyrimidines ,Tissue Distribution ,Gemcitabine ,JAK inhibitor ,Momelotinib ,Phase 1 ,TBK1 inhibitor ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.
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- 2019
36. A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer
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Tuli, Richard, Shiao, Stephen L, Nissen, Nicholas, Tighiouart, Mourad, Kim, Sungjin, Osipov, Arsen, Bryant, Miranda, Ristow, Lindsey, Placencio-Hickok, Veronica, Hoffman, David, Rokhsar, Sepehr, Scher, Kevin, Klempner, Samuel J, Noe, Paul, Davis, MJ, Wachsman, Ashley, Lo, Simon, Jamil, Laith, Sandler, Howard, Piantadosi, Steven, and Hendifar, Andrew
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Digestive Diseases ,Genetics ,Pancreatic Cancer ,Clinical Research ,Cancer ,Rare Diseases ,6.5 Radiotherapy and other non-invasive therapies ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Benzimidazoles ,Combined Modality Therapy ,Deoxycytidine ,Female ,Humans ,Male ,Microsatellite Instability ,Middle Aged ,Mutation ,Neoplasm Metastasis ,Neoplasm Staging ,Pancreatic Neoplasms ,Poly (ADP-Ribose) Polymerase-1 ,Poly(ADP-ribose) Polymerase Inhibitors ,Poly(ADP-ribose) Polymerases ,Prognosis ,Radiotherapy ,Treatment Outcome ,Gemcitabine ,Parp inhibitor ,Radiation ,Pancreas cancer ,Veliparib ,Public Health and Health Services ,Clinical sciences ,Epidemiology - Abstract
BackgroundLocally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC.MethodsThis was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status.FindingsThirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2-27.2) and 14 months (95% CI: 10.0-21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS.InterpretationThis is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.
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- 2019
37. Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models
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Tu, Mei-Juan, Ho, Pui Yan, Zhang, Qian-Yu, Jian, Chao, Qiu, Jing-Xin, Kim, Edward J, Bold, Richard J, Gonzalez, Frank J, Bi, Huichang, and Yu, Ai-Ming
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Digestive Diseases ,Genetics ,Pancreatic Cancer ,Rare Diseases ,Biotechnology ,Cancer ,6.1 Pharmaceuticals ,5.1 Pharmaceuticals ,Albumins ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,Cell Proliferation ,DNA-Binding Proteins ,Deoxycytidine ,Dose-Response Relationship ,Drug ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Mice ,Inbred NOD ,Mice ,Nude ,Mice ,SCID ,Mice ,Transgenic ,MicroRNAs ,Paclitaxel ,Pancreatic Neoplasms ,Prodrugs ,Signal Transduction ,Tumor Burden ,Xenograft Model Antitumor Assays ,Gemcitabine ,miR-1291 ,Pancreatic cancer ,PDX model ,ARID3B ,Gemcitabine plus nab-paclitaxel ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70-90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.
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- 2019
38. Normalized Retention Time for Targeted Analysis of the DNA Adductome.
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Cui, Yuxiang, Wang, Pengcheng, Yu, Yang, Yuan, Jun, and Wang, Yinsheng
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Chromatography ,High Pressure Liquid ,DNA Adducts ,Deoxyadenosines ,Deoxycytidine ,Deoxyguanosine ,Hydrophobic and Hydrophilic Interactions ,Nanotechnology ,Stereoisomerism ,Tandem Mass Spectrometry ,Thymidine - Abstract
A wide spectrum of DNA lesions can be generated from byproducts of endogenous metabolism and/or from environmental exposure. A DNA adductomic approach for the robust quantification of DNA adducts in cellular and tissue DNA may facilitate the use of DNA adducts for biomonitoring studies and enable comprehensive assessment about DNA repair. Normalized retention time (iRT) has been widely used in scheduled selected-reaction monitoring (SRM) methods for highly sensitive and high-throughput analyses of protein samples in complicated matrices. By using a similar method, we established the iRT scores for 36 modified nucleosides from the retention times of the four canonical 2-deoxynucleosides on a nanoflow liquid chromatography-nanospray ionization-tandem mass spectrometry (nLC-NSI-MS/MS) system. The iRT scores facilitated reliable prediction of retention time and were employed for establishing a scheduled SRM method for quantitative assessment of a subset of the DNA adductome. The quantification results of the scheduled SRM method were more accurate and precise than those from an unscheduled method.
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- 2018
39. An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice
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Edderkaoui, Mouad, Chheda, Chintan, Soufi, Badr, Zayou, Fouzia, Hu, Robert W, Ramanujan, V Krishnan, Pan, Xinlei, Boros, Laszlo G, Tajbakhsh, Jian, Madhav, Anisha, Bhowmick, Neil A, Wang, Qiang, Lewis, Michael, Tuli, Richard, Habtezion, Aida, Murali, Ramachandran, and Pandol, Stephen J
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Rare Diseases ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Cancer ,Pancreatic Cancer ,Digestive Diseases ,Biotechnology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Antineoplastic Agents ,Apoptosis ,Carcinoma ,Pancreatic Ductal ,Cell Line ,Tumor ,Cell Proliferation ,Deoxycytidine ,Gene Expression Regulation ,Neoplastic ,Glycogen Synthase Kinase 3 beta ,Histone Deacetylase Inhibitors ,Humans ,Mice ,Pancreas ,Pancreatic Neoplasms ,Neoplasm ,EMT ,Chemotherapeutic Agent ,Gemcitabine ,Clinical Sciences ,Neurosciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology - Abstract
Background & aimsGrowth, progression, and drug resistance of pancreatic ductal adenocarcinomas (PDACs) have been associated with increased levels and activity of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs). We designed and synthesized molecules that simultaneously inhibit the activities of both enzymes. We tested the effects of one of these molecules, Metavert, in pancreatic cancer cells and mice with pancreatic tumors.MethodsWe tested the ability of Metavert to bind GSK3B and HDACs using surface plasmon resonance. MIA PaCa-2, Bx-PC3, HPAF-II, and HPDE6 cell lines were incubated with different concentrations of Metavert, with or without paclitaxel or gemcitabine, or with other inhibitors of GSK3B and HDACs; cells were analyzed for apoptosis and migration and by immunoblotting, immunofluorescence, and real-time polymerase chain reaction. Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) mice (2 months old) were given injections of Metavert (5 mg/kg, 3 times/week) or vehicle (control). B6.129J mice with tumors grown from UN-KPC961-Luc cells were given injections of Metavert or vehicle. Tumors and metastases were counted and pancreata were analyzed by immunohistochemistry. Glucose metabolism was measured using 13C-glucose tracer and mass spectroscopy and flow cytometry. Cytokine levels in blood samples were measured using multiplexing enzyme-linked immunosorbent assay.ResultsMetavert significantly reduced survival of PDAC cells but not nontransformed cells; the agent reduced markers of the epithelial-to-mesenchymal transition and stem cells in PDAC cell lines. Cells incubated with Metavert in combination with irradiation and paclitaxel or gemcitabine had reduced survival compared with cells incubated with either agent alone; Metavert increased killing of drug-resistant PDAC cells by paclitaxel and gemcitabine. PDAC cells incubated with Metavert acquired normalized glucose metabolism. Administration of Metavert (alone or in combination with gemcitibine) to KPC mice or mice with syngeneic tumors significantly increased their survival times, slowed tumor growth, prevented tumor metastasis, decreased tumor infiltration by tumor-associated macrophages, and decreased blood levels of cytokines.ConclusionsIn studies of PDAC cells and 2 mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACs (Metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.
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- 2018
40. Pembrolizumab Combined With Either Docetaxel or Gemcitabine in Patients With Advanced or Metastatic Platinum-Refractory Urothelial Cancer: Results From a Phase I Study
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Parikh, Mamta, Pan, Chong-Xian, Beckett, Laurel A, Li, Yueju, Robles, Daniel A, Aujla, Pawandeep K, and Lara, Primo N
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Digestive Diseases ,Cancer ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Transitional Cell ,Deoxycytidine ,Docetaxel ,Drug Resistance ,Neoplasm ,Feasibility Studies ,Female ,Humans ,Kaplan-Meier Estimate ,Male ,Maximum Tolerated Dose ,Middle Aged ,Neutropenia ,Platinum Compounds ,Progression-Free Survival ,Response Evaluation Criteria in Solid Tumors ,Urologic Neoplasms ,Gemcitabine ,Checkpoint inhibition ,Chemotherapy ,Immunotherapy ,Platinum-refractory ,Urothelial Carcinoma ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
IntroductionCytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab.Patients and methodsPatients with advanced, platinum-refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose-limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression-free survival (PFS).ResultsTwelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment-related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively.ConclusionPembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum-refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.
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- 2018
41. 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses the growth of human liver cancer HepG2 cells in vitro: Involvement of cell signaling factors
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Yamaguchi, Masayoshi and Hankinson, Oliver
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Biochemistry and Cell Biology ,Biological Sciences ,Rare Diseases ,Agent Orange & Dioxin ,Digestive Diseases ,Liver Disease ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Antineoplastic Combined Chemotherapy Protocols ,Basic Helix-Loop-Helix Transcription Factors ,Cell Proliferation ,DNA Damage ,Deoxycytidine ,Dose-Response Relationship ,Drug ,Drug Synergism ,Hep G2 Cells ,Humans ,Liver Neoplasms ,Polychlorinated Dibenzodioxins ,Receptors ,Aryl Hydrocarbon ,Signal Transduction ,Gemcitabine ,2 ,3 ,7 ,8-tetrachlorodibenzo-p-dioxin ,cell proliferation ,cell death ,colony formation ,HepG2 cells ,cell signaling ,carcinogenesis ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
The aryl hydrocarbon receptor (AHR) is transcriptionally active in the form of a heterodimer with the AHR nuclear translocator, which then binds to the xenobiotic responsive element. AHR was originally discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD). In this study, we investigated whether TCDD regulates the growth of human liver cancer HepG2 cells in vitro. TCDD (0.1‑100 nM) was found to exert suppressive effects on the colony formation and proliferation of HepG2 cells, and stimulatory effects on the death of HepG2 cells when the cells reached subconfluence. The effects of TCDD on the HepG2 cells were abolished by culture with CH223191, an inhibitor of AHR signaling. The effects of TCDD were dependent on the concentration of serum, which contains various signaling factors. The effects of TCDD were not potentiated by culture with tumor necrosis factor‑α, which activates the signaling of nuclear factor‑κB (NF‑κB). The results of western blot analysis revealed that TCDD increased the protein levels of p53, Rb, p21, and regucalcin, which are suppressors of the growth of tumor cells. Moreover, TCDD enhanced the NF‑κB p65, β‑catenin, signal transducer and activator of transcription 3 (STAT3), Ras and Akt levels. Thus, the findings of this study indicate that TCDD may suppress liver cancer cell growth through various signaling pathways, mediated by AHR and its‑related co‑factors. Of note, the effects of TCDD were found to be potentiated by gemcitabine, which induces nuclear DNA damage in cancer cells, suggesting that their combined use may have potential as a suppressor of tumor cell growth.
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- 2018
42. Gemcitabine: An Alternative Treatment for Oxaliplatin-Resistant Colorectal Cancer.
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Chocry, Mathieu, Leloup, Ludovic, Parat, Fabrice, Messé, Mélissa, Pagano, Alessandra, and Kovacic, Hervé
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IN vitro studies , *DRUG efficacy , *IN vivo studies , *CANCER chemotherapy , *DEOXYCYTIDINE , *APOPTOSIS , *ANTINEOPLASTIC agents , *COLORECTAL cancer , *CANCER patients , *TREATMENT effectiveness , *ORGANOPLATINUM compounds , *TREATMENT failure , *CELLULAR signal transduction , *CELL proliferation , *TRANSFERASES , *OXALIPLATIN , *ALTERNATIVE medicine , *MITOGEN-activated protein kinases , *REACTIVE oxygen species , *DRUG resistance in cancer cells , *CYTOTOXINS - Abstract
Simple Summary: Colorectal cancer is the third most common cancer worldwide. The treatment of the advanced stages is based on poly-chemotherapies, including oxaliplatin. However, the development of resistance to chemotherapy is observed in 50% of cases, leading to treatment failures. A better understanding of the resistance mechanisms is therefore crucial to improve treatment efficiency and patient survival. In our previous work, showed that ROS production and the p38 MAPK pathway were strongly involved in resistance to oxaliplatin. In this study, we tested several chemotherapies and observed that only gemcitabine efficiently treated oxaliplatin-resistant cancer cells. Indeed, gemcitabine was able to induce apoptosis by inhibiting both the Akt and p38 MAPK pathways. Taken together, our results show that gemcitabine could be an interesting therapeutic option for patients with oxaliplatin-resistant tumors. Resistance to treatments is one of the leading causes of cancer therapy failure. Oxaliplatin is a standard chemotherapy used to treat metastatic colorectal cancer. However, its efficacy is greatly reduced by the development of resistances. In a previous study, we deciphered the mechanisms leading to oxaliplatin resistance and highlighted the roles played by ROS production and the p38 MAPK pathway in this phenomenon. In this report, we studied the effects of different chemotherapy molecules on our oxaliplatin-resistant cells to identify alternative treatments. Among all the studied molecules, gemcitabine was the only one to present a major cytotoxic effect on oxaliplatin-resistant cancer cells both in vivo and in vitro. However, the combination of oxaliplatin and gemcitabine did not present any major interest. Indeed, the study of combination efficiency using Chou and Talalay's method showed no synergy between oxaliplatin and gemcitabine. Using PamGene technology to decipher gemcitabine's effects on oxaliplatin-resistant cells, we were able to show that gemcitabine counteracts chemoresistance by strongly inhibiting the Akt and src/p38 MAPK pathways, leading to apoptosis induction and cell death. In view of these results, gemcitabine could be an interesting alternative therapy for patients with colorectal cancer not responding to oxaliplatin-based protocols such as FOLFOX. [ABSTRACT FROM AUTHOR]
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- 2022
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43. Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.
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Tanaka, Kazuhiro, Machida, Ryunosuke, Kawai, Akira, Nakayama, Robert, Tsukushi, Satoshi, Asanuma, Kunihiro, Matsumoto, Yoshihiro, Hiraga, Hiroaki, Hiraoka, Koji, Watanuki, Munenori, Yonemoto, Tsukasa, Abe, Satoshi, Katagiri, Hirohisa, Nishida, Yoshihiro, Nagano, Akihito, Suehara, Yoshiyuki, Kawashima, Hiroyuki, Kawano, Masanori, Morii, Takeshi, and Hatano, Hiroshi
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RESEARCH , *CLINICAL trials , *DOXORUBICIN , *RESEARCH methodology , *NEUTROPENIA , *ANTINEOPLASTIC agents , *IFOSFAMIDE , *DEOXYCYTIDINE , *EVALUATION research , *SOFT tissue tumors , *COMPARATIVE studies , *RANDOMIZED controlled trials , *RESEARCH funding , *SARCOMA - Abstract
Background: This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS).Methods: Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS.Results: Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80-8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3-4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD.Conclusions: Although GD had relatively mild toxicity, the regimen-as administered in this study-should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk.Clinical Trial Registration: jRCTs031180003. [ABSTRACT FROM AUTHOR]- Published
- 2022
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44. A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01.
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Sahai, Vaibhav, Griffith, Kent A., Beg, Muhammad S., Shaib, Walid L., Mahalingam, Devalingam, Zhen, David B., Deming, Dustin A., and Zalupski, Mark M.
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RESEARCH , *CLINICAL trials , *RESEARCH methodology , *DEOXYCYTIDINE , *ANTINEOPLASTIC agents , *EVALUATION research , *COMPARATIVE studies , *RANDOMIZED controlled trials , *CISPLATIN , *RESEARCH funding ,BILE duct tumors - Abstract
Background: Gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors.Methods: In this phase 2 trial, patients 18 years or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status 0-1 were randomized across six academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks.Results: Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5% women with a median age of 62.5 years. The observed primary outcome of 6-month progression-free survival (PFS) rates in the evaluable population was 59.4% in Arm A and 21.2% in Arm B. The median PFS and overall survival (OS) in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade 3 or higher hematologic adverse event was neutropenia in 34.3% (Arm A) and nonhematologic adverse events were fatigue (8.6% Arm A) and elevated transaminases (9.1% Arm B).Conclusions: The addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggests benefit in a small cohort of patients. [ABSTRACT FROM AUTHOR]- Published
- 2022
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45. Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance.
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Chiou, Shin-Heng, Dorsch, Madeleine, Kusch, Eva, Naranjo, Santiago, Kozak, Margaret M, Koong, Albert C, Winslow, Monte M, and Grüner, Barbara M
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Tumor Cells ,Cultured ,Animals ,Mice ,Knockout ,Humans ,Mice ,Adenocarcinoma ,Carcinoma ,Pancreatic Ductal ,Pancreatic Neoplasms ,HMGA2 Protein ,Deoxycytidine ,Antimetabolites ,Antineoplastic ,Prognosis ,Tissue Array Analysis ,Survival Rate ,Cell Proliferation ,Drug Resistance ,Neoplasm ,Cancer ,Rare Diseases ,Pancreatic Cancer ,Digestive Diseases ,2.1 Biological and endogenous factors - Abstract
Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
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- 2018
46. Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers
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Sen, Shiraj, Kato, Shumei, Agarwal, Rishi, Piha-Paul, Sarina, Hess, Kenneth, Karp, Daniel, Janku, Filip, Fu, Siqing, Naing, Aung, Pant, Shubham, Falchook, Gerald, Tang, Chad, Wu, Xifeng, Ye, Yuanqing, Tsimberidou, Apostolia, Subbiah, Vivek, Kurzrock, Razelle, Byers, Lauren, Westin, Shannon, Lim, JoAnn, Bean, Stacie, Bass, Allison, Nguyen, Ly, Meric-Bernstam, Funda, and Hong, David
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Albumins ,Antineoplastic Combined Chemotherapy Protocols ,Bevacizumab ,Deoxycytidine ,Drug Administration Schedule ,Female ,Humans ,Male ,Maximum Tolerated Dose ,Middle Aged ,Neoplasms ,Paclitaxel ,Polymorphism ,Genetic ,Treatment Outcome ,Vascular Endothelial Growth Factor A ,Young Adult ,Gemcitabine ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.
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- 2018
47. Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer
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Kawaguchi, Kei, Miyake, Kentaro, Han, Qinghong, Li, Shukuan, Tan, Yuying, Igarashi, Kentaro, Lwin, Thinzar M, Higuchi, Takashi, Kiyuna, Tasuku, Miyake, Masuyo, Oshiro, Hiromichi, Bouvet, Michael, Unno, Michiaki, and Hoffman, Robert M
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Orphan Drug ,Cancer ,Digestive Diseases ,Pancreatic Cancer ,Rare Diseases ,Animals ,Antimetabolites ,Antineoplastic ,Antineoplastic Combined Chemotherapy Protocols ,Carbon-Sulfur Lyases ,Deoxycytidine ,Drug Administration Schedule ,Drug Resistance ,Neoplasm ,Gene Expression ,Humans ,Injections ,Intraperitoneal ,Male ,Methionine ,Mice ,Mice ,Nude ,Molecular Targeted Therapy ,Pancreatic Neoplasms ,Recombinant Proteins ,Tumor Burden ,Xenograft Model Antitumor Assays ,Gemcitabine ,Recombinant methioninase ,methionine dependence ,pancreatic cancer ,patient-derived orthotopic xenograft ,nude mice ,orthotopic ,gemcitabine ,precision therapy ,Developmental Biology ,Biochemistry and cell biology - Abstract
Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.
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- 2018
48. Growth of doxorubicin‐resistant undifferentiated spindle‐cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase
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Igarashi, Kentaro, Li, Shukuan, Han, Qinghong, Tan, Yuying, Kawaguchi, Kei, Murakami, Takashi, Kiyuna, Tasuku, Miyake, Kentaro, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Singh, Arun S, Elliott, Irmina A, Russell, Tara A, Eckardt, Mark A, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Biotechnology ,Cancer ,Rare Diseases ,Orphan Drug ,Animals ,Carbon-Sulfur Lyases ,Deoxycytidine ,Disease Models ,Animal ,Docetaxel ,Doxorubicin ,Female ,Indazoles ,Melanoma ,Mice ,Mice ,Nude ,Pyrimidines ,Sarcoma ,Ewing ,Sulfonamides ,Taxoids ,Xenograft Model Antitumor Assays ,doxorubicin ,patient-derived orthotopic xenograft ,PDOX ,recombinant methioninase ,resistant ,undifferentiated spindle-cell sarcoma ,Gemcitabine ,Biochemistry and Cell Biology ,Medical Physiology ,Biochemistry & Molecular Biology - Abstract
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.
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- 2018
49. The 4-N-acyl and 4-N-alkyl gemcitabine analogues with silicon-fluoride-acceptor: Application to 18F-Radiolabeling
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Gonzalez, Cesar, Sanchez, Andersson, Collins, Jeffrey, Lisova, Ksenia, Lee, Jason T, van Dam, R Michael, Barbieri, M Alejandro, Ramachandran, Cheppail, and Wnuk, Stanislaw F
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Organic Chemistry ,Chemical Sciences ,Rare Diseases ,Digestive Diseases ,Animals ,Cell Line ,Tumor ,Deoxycytidine ,Fluorides ,Fluorine Radioisotopes ,Gastrointestinal Tract ,HEK293 Cells ,Humans ,Kidney ,Liver ,Mice ,Positron-Emission Tomography ,Silicon Compounds ,Tissue Distribution ,Gemcitabine ,Medicinal and Biomolecular Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
The coupling of gemcitabine with functionalized carboxylic acids using peptide coupling conditions afforded 4-N-alkanoyl analogues with a terminal alkyne or azido moiety. Reaction of 4-N-tosylgemcitabine with azidoalkyl amine provided 4-N-alkyl gemcitabine with a terminal azido group. Click reaction with silane building blocks afforded 4-N-alkanoyl or 4-N-alkyl gemcitabine analogues suitable for fluorination. RP-HPLC analysis indicated better chemical stability of 4-N-alkyl gemcitabine analogues versus 4-N-alkanoyl analogues in acidic aqueous conditions. The 4-N-alkanoyl gemcitabine analogues showed potent cytostatic activity against L1210 cell line, but cytotoxicity of the 4-N-alkylgemcitabine analogues was low. However, 4-N-alkanoyl and 4-N-alkyl analogues had comparable antiproliferative activities in the HEK293 cells. The 4-N-alkyl analogue with a terminal azide group was shown to be localized inside HEK293 cells by fluorescence microscopy after labelling with Fluor 488-alkyne. The [18F]4-N-alkyl or alkanoyl silane gemcitabine analogues were successfully synthesized using microscale and conventional silane-labeling radiochemical protocols. Preliminary positron-emission tomography (PET) imaging in mice showed the biodistribution of [18F]4-N-alkyl to have initial concentration in the liver, kidneys and GI tract followed by increasing signal in the bone.
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- 2018
50. A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers
- Author
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Davis, Elizabeth J, Griffith, Kent A, Kim, Edward J, Ruch, Joshua M, McDonnell, Kevin J, and Zalupski, Mark M
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Pancreatic Cancer ,Clinical Trials and Supportive Activities ,Orphan Drug ,Digestive Diseases ,Cancer ,Clinical Research ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adenocarcinoma ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Biliary Tract Neoplasms ,Cisplatin ,Deoxycytidine ,Disease-Free Survival ,Dose-Response Relationship ,Drug ,Drug Administration Schedule ,Female ,Fluorouracil ,Humans ,Infusions ,Intravenous ,Male ,Middle Aged ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Neoplasm Staging ,Pancreatic Neoplasms ,Patient Selection ,Prognosis ,Risk Assessment ,Survival Analysis ,Treatment Outcome ,Gemcitabine ,metastatic pancreatic cancer ,metastatic biliary cancer ,gemcitabine ,cisplatin ,5-fluorouracil ,Dentistry ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
ObjectivesCombinations of gemcitabine, 5-fluorouracil (5-FU), and platinum have demonstrated improved outcomes compared with singlet chemotherapy in pancreatic and biliary cancers. This phase II study examined efficacy and safety of a novel schedule of cisplatin, fixed-dose-rate gemcitabine and infusional 5-FU.Materials and methodsPatients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received 1 cytotoxic regimen for advanced disease, were treated with gemcitabine 1000 mg/m intravenously (IV) over 100 minutes, cisplatin 35 mg/m IV over 30 minutes, and 5-FU 2400 mg/m IV over 48 hours on day 1 of a 14-day cycle. Patients were treated until disease progression or for 12 cycles. After 12 cycles, patients with stable or responding disease could continue gemcitabine and 5-FU. The primary endpoint was objective response.ResultsThirty-nine patients were treated: 8 with biliary cancer (all untreated) and 31 with pancreatic cancer (17 untreated, 14 previously treated). Best response in 25 untreated patients was partial response in 40%, stable disease in 40%, and progressive disease in 20%. In 14 previously treated pancreatic patients, best response was partial response in 7%, stable disease in 50%, and progressive disease in 43%. Median overall survival in untreated patients was 10.3 versus 4.9 months in previously treated patients. Adverse events were primarily uncomplicated hematologic toxicity, ≥grade 3 neutropenia (54%), anemia (21%), and thrombocytopenia (13%).ConclusionBiweekly cisplatin, fixed-dose-rate gemcitabine, and infusional 5-FU demonstrated a high response rate and were well tolerated, encouraging further investigation of this regimen in metastatic pancreatic and biliary cancers.
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- 2018
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