9 results on '"Uzunparmak, B."'
Search Results
2. Comment on: α-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study
- Author
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Sahin, I H, primary and Uzunparmak, B, additional
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- 2015
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3. Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts.
- Author
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DiPeri TP, Evans KW, Wang B, Zhao M, Akcakanat A, Raso MG, Rizvi YQ, Zheng X, Korkut A, Varadarajan K, Uzunparmak B, Dumbrava EE, Pant S, Ajani JA, Pohlmann PR, Jensen VB, Javle M, Rodon J, and Meric-Bernstam F
- Subjects
- Animals, Humans, Mice, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Xenograft Model Antitumor Assays, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Receptor, ErbB-2 antagonists & inhibitors
- Abstract
Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance., Significance: We demonstrate that PDXs can be developed from pretreatment and postprogression biopsies in clinical trials and may represent a powerful preclinical tool. We identified amplification of MET as a potential mechanism of acquired resistance to the HER2 inhibitor zanidatamab and MET inhibitors alone and in combination as a therapeutic strategy. This article is featured in Selected Articles from This Issue, p. 695., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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4. Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing.
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Nowlen CJ, Daniels M, Uzunparmak B, Ileana Dumbrava EE, Yuan Y, Patel KP, Rayes N, Harkenrider J, Wathoo C, Veazie J, Luna KA, Wang W, Horombe C, Javle M, Ahnert JR, Yap TA, Arun B, Lu KH, and Meric-Bernstam F
- Abstract
Introduction: Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 ( BRCA1/2 ) via tumor-only profiling, then determined the germline testing outcomes for those patients., Methods: A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing., Results: This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing., Conclusion: Tumor-only testing is likely to identify P/LPVs in BRCA1/2 . Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations., Competing Interests: Conflict of Interest: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships may not relate to the subject matter of this manuscript. Ecaterina E. Ileana Dumbrava reports the following: Consulting: Catamaran Bio; Advisory Committee: BOLT Therapeutics; and Sponsored Research (to the institution): Bayer HealthCare Pharmaceuticals Inc., Immunocore LTD, Amgen, Aileron Therapeutics, Compugen LTD, TRACON Pharmaceuticals Inc., Unum Therapeutics, Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc., Sanofi, and Astex Therapetics. Ying Yuan reports the following: Consulting: AbbVie, Amgen, Bexion Pharmaceuticals, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, GT Medical Technologies, Mirati Therapeutics, Servier Pharmaceuticals, Starpax Pharmaceuticals, and Vertex Pharmaceuticals; and Honoraria: Blueprint. Milind Javle reports the following: Advisory Committee: OrgiMed, More Health, EDO; Sponsored Research (self): QED, Novartis, and Meclun; Sponsored Research (to the institution): Lily and Arqule; Honoraria: Taiho, Seattle Genetics, Merck. Jordi Rodon Ahnert reports the following: Advisory Committee: Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, NovellusDX, IONCTURA SA, Kisoji Biotechnology, Inc.; Sponsored Research (to the institution): Bayer, Novartis, Blueprint Medicines, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenniums, GlaxoSmithKline, Ipsen; Travel Reimbursement: ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Consortium, Janssen, Molecular Partners; Other: European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline. Timothy A. Yap reports the following: Consulting: AstraZeneca, Almac, Aduro, Artios, Athena, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, GLG, Guidepoint, Ignyta, I-Mab, ImmuneSensor, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Seattle Genetics, Varian, Zai Labs, and ZielBio; Sponsored Research (to the institution): AstraZeneca, Artios, Bayer, Beigene, BioNTech, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Repare, Ribon Therapeutics, Regeneron, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vivace. Banu Arun reports the following: Sponsored Research (to the institution): AstraZeneca; and Advisory Committee: AbbVie (non-paid steering committee member for BROCADE 3 study). Funda Meric-Bernstam reports the following: Consulting: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; Advisory Committee: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; Sponsored Research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co.; Honoraria: Chugai Biopharmaceuticals; and Other (Travel Related): European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO). The remaining authors have no disclosures.
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- 2024
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5. Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic-induced necroptosis.
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Uzunparmak B, Gao M, Lindemann A, Erikson K, Wang L, Lin E, Frank SJ, Gleber-Netto FO, Zhao M, Skinner HD, Newton J, Sikora AG, Myers JN, and Pickering CR
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- Apoptosis drug effects, Apoptosis Regulatory Proteins metabolism, Biomimetics, Caspase 8 genetics, Caspase 8 physiology, Caspase Inhibitors metabolism, Caspase Inhibitors pharmacology, Caspases metabolism, Cell Line, Tumor, Databases, Genetic, Dipeptides metabolism, Dipeptides pharmacology, Humans, Indoles metabolism, Indoles pharmacology, Intracellular Signaling Peptides and Proteins metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Necroptosis genetics, Squamous Cell Carcinoma of Head and Neck genetics, Caspase 8 metabolism, Necroptosis physiology, Squamous Cell Carcinoma of Head and Neck metabolism
- Abstract
Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.
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- 2020
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6. Pancreatic cancer microenvironment: a current dilemma.
- Author
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Uzunparmak B and Sahin IH
- Abstract
Pancreatic cancer is one of the leading causes of cancer-related death in the United States and survival outcomes remain dismal despite significant advances in molecular diagnostics and therapeutics in clinical practice. The microenvironment of pancreatic cancer carries unique features with increased desmoplastic reaction and is infiltrated by regulatory T cells and myeloid-derived suppressor cells which negatively impact the effector immune cells. Current evidence suggests that stellate cell-induced hypovascular stroma may have direct effects on aggressive behavior of pancreatic cancer. Preclinical studies suggested improvement in drug delivery to cancer cells with stroma modifying agents. However these findings so far have not been confirmed in clinical trials. In this article, we elaborate current-state-of-the science of the pancreatic cancer microenvironment and its impact on molecular behavior of cancer cells, chemotherapy resistance and druggability of stroma elements in combination with other agents to enhance the efficacy of therapeutic approaches.
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- 2019
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7. Comment on "ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer".
- Author
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Uzunparmak B and Sahin IH
- Subjects
- Drug Resistance, Neoplasm, Humans, p38 Mitogen-Activated Protein Kinases, Colorectal Neoplasms, Proto-Oncogene Proteins B-raf
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- 2018
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8. Structure/function analysis of PARP-1 in oxidative and nitrosative stress-induced monomeric ADPR formation.
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Buelow B, Uzunparmak B, Paddock M, and Scharenberg AM
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- Animals, Catalysis, Cell Line, Chickens, DNA Damage, Poly(ADP-ribose) Polymerases chemistry, Structure-Activity Relationship, Adenosine Diphosphate Ribose biosynthesis, Nitrosation, Oxidative Stress, Poly(ADP-ribose) Polymerases metabolism
- Abstract
Poly adenosine diphosphate-ribose polymerase-1 (PARP-1) is a multifunctional enzyme that is involved in two major cellular responses to oxidative and nitrosative (O/N) stress: detection and response to DNA damage via formation of protein-bound poly adenosine diphosphate-ribose (PAR), and formation of the soluble 2(nd) messenger monomeric adenosine diphosphate-ribose (mADPR). Previous studies have delineated specific roles for several of PARP-1's structural domains in the context of its involvement in a DNA damage response. However, little is known about the relationship between the mechanisms through which PARP-1 participates in DNA damage detection/response and those involved in the generation of monomeric ADPR. To better understand the relationship between these events, we undertook a structure/function analysis of PARP-1 via reconstitution of PARP-1 deficient DT40 cells with PARP-1 variants deficient in catalysis, DNA binding, auto-PARylation, and PARP-1's BRCT protein interaction domain. Analysis of responses of the respective reconstituted cells to a model O/N stressor indicated that PARP-1 catalytic activity, DNA binding, and auto-PARylation are required for PARP-dependent mADPR formation, but that BRCT-mediated interactions are dispensable. As the BRCT domain is required for PARP-dependent recruitment of XRCC1 to sites of DNA damage, these results suggest that DNA repair and monomeric ADPR 2(nd) messenger generation are parallel mechanisms through which PARP-1 modulates cellular responses to O/N stress.
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- 2009
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9. Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer.
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van der Vliet HJ, Koon HB, Yue SC, Uzunparmak B, Seery V, Gavin MA, Rudensky AY, Atkins MB, Balk SP, and Exley MA
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- Adult, Aged, Carcinoma, Renal Cell immunology, Dose-Response Relationship, Drug, Female, Flow Cytometry, Humans, Interleukin-2 Receptor alpha Subunit metabolism, Kidney Neoplasms immunology, Killer Cells, Natural drug effects, Male, Melanoma immunology, Middle Aged, T-Lymphocytes, Regulatory drug effects, Carcinoma, Renal Cell drug therapy, Dendritic Cells drug effects, Interleukin-2 therapeutic use, Kidney Neoplasms drug therapy, Lymphocyte Subsets drug effects, Melanoma drug therapy
- Abstract
Purpose: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored., Experimental Design: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4(+)CD25(+) regulatory-type T cells., Results: The frequency of both circulating myeloid DC1 and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4(-) iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4(+)CD25(+) T cells, including CD4(+)Foxp3(+) T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4(+)CD25(+) T cells in response to IL-2. Functionally, patient CD25(+) T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25(+) T cells and mostly failed to Th2 polarize iNKT., Conclusions: Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.
- Published
- 2007
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