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The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Active targeting to cancer involves exploiting specific interactions between receptors on the surface of cancer cells and targeting moieties conjugated to the surface of vectors such that site-specific delivery is achieved. Prostate specific membrane antigen (PSMA) has proved to be an excellent target for active targeting to prostate cancer. We report the synthesis and use of a PSMA-specific ligand (Glu-NH-CO-NH-Lys) for the site-specific delivery of brusatol- and docetaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles to prostate cancer. The PSMA targeting ligand covalently linked to PLGA-PEG 3400 was blended with methoxyPEG-PLGA to prepare brusatol- and docetaxel-loaded nanoparticles with different surface densities of the targeting ligand. Flow cytometry was used to evaluate the impact of different surface densities of the PSMA targeting ligand in LNCaP prostate cancer cells at 15 min and 2 h. Cytotoxicity evaluations of the targeted nanoparticles reveal differences based on PSMA expression in PC-3 and LNCaP cells. In addition, levels of reactive oxygen species (ROS) were measured using the fluorescent indicator, H 2 DCFDA, by flow cytometry. PSMA-targeted nanoparticles loaded with docetaxel and brusatol showed increased ROS generation in LNCaP cells compared to PC-3 at different time points. Furthermore, the targeted nanoparticles were evaluated in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors. Evaluation of the percent relative tumor volume show that brusatol-containing nanoparticles show great promise in inhibiting tumor growth. Our data also suggest that the dual drug-loaded targeted nanoparticle platform improves the efficacy of docetaxel in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests: SKA reports that funding for the work was provided by NIGMS/NIH, USA. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

The goal of the study was to fabricate folic acid functionalized docetaxel (DOC)/erlotinib (ERL)-loaded solid lipid nanoparticles (SLNs) to synergistically increase the anticancer activity against triple-negative breast cancer. DOC/ERL-SLNs were prepared by the high shear homogenization - ultrasound dispersion method (0.1 % w/v for DOC, and 0.3 %w/v for ERL) and optimized using Plackett Burman Design (PBD) followed by Box Behnken Design (BBD). The optimized SLNs demonstrated particle size < 200 nm, PDI < 0.35, and negative zeta potential with entrapment and loading efficiency of ∼80 and ∼4 %, respectively. The SLNs and folic acid functionalized SLNs (FA-SLNs) showed sustained release for both drugs, followed by Higuchi and Korsemeyer-Peppas drug release models, respectively. Further, the in vitro pH-stat lipolysis model demonstrated an approximately 3-fold increase in the bioaccessibility of drugs from SLNs compared to suspension. The TEM images revealed the spherical morphology of the SLNs. DOC/ERL loaded SLNs showed dose- and time-dependent cytotoxicity and exhibited a synergism at a molar ratio of 1:3 in TNBC with a combination index of 0.35 and 0.37, respectively. FA-DOC/ERL-SLNs showed enhanced anticancer activity as evidenced by MMP and ROS assay and further inhibited the colony-forming ability and the migration capacity of TNBC cells. Conclusively, the study has shown that SLNs are encouraging systems to improve the pharmaceutical attributes of poorly bioavailable drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: We previously reported that S-1 and low-dose docetaxel (DOC) (N-1 study, phase II trial) could be a well-tolerated and effective neoadjuvant chemotherapies (NACs) for patients with operable breast cancer. Herein, we analyzed the long-term outcomes and developed clinicopathological and molecular predictors of pathological complete response (pCR)., Patients and Methods: Eighty-three patients received S-1 (40 mg/m 2 orally on days 1-14) and DOC (40 mg/m 2 intravenously on day 1) every 3 weeks for 4 to 8 cycles. Disease-free survival (DFS) and overall survival (OS) were analyzed for each population with a pCR status. To assess the relationship between pCR and clinicopathological factors such as tumor-infiltrating lymphocytes (TILs, 1+ <10%, 2+ 10%-50%, and 3+ >50%) and nuclear grade (NG), microarray was used to compare the microRNA profiles of the pCR and non-pCR groups using core needle biopsy specimens., Results: With a median follow-up duration of 99.0 (range, 9.0-129.0) months, the 5-year DFS and OS rates were 80.7% and 90.9%, respectively. The 5-year OS rate of the pCR group was significantly better than that of the non-pCR group (100% vs. 86.2%, p = .0176). Specifically, in triple-negative patients, the difference was significant (100% vs. 60.0%, p = .0224). Multivariate analysis revealed that high TILs (≥2-3+) and NG 2-3 independently predicted pCR. Microarray data revealed that 3 miRNAs (miR-215-5p, miR-196a-5p, and miR-196b-5p) were significantly upregulated in the pCR group., Conclusion: Our NAC regimen achieved favorable long-term outcomes and significantly improved OS in the pCR group. High TILs, NG 2-3, and some miRNAs may be predictors of pCR., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nanoparticle's success as drug delivery systems for cancer treatment has been achieved through passive targeting mechanisms. However, tumor heterogeneity and rapid drug clearance limit the treatment efficacy. Improved outcomes and selective drug release can be achieved by grafting ligands at the surface of nanocarriers that bind molecules overexpressed in the tumor microenvironment (TME). In this work, we developed a docetaxel-loaded nanoemulsions (NEs) binding an anti-netrin-1 monoclonal antibody (NP137) to selectively target the netrin-1 protein overexpressed in many different tumors. The goal is to refine a combined approach utilizing NP137 and docetaxel as an improved tumor-targeting chemotherapeutic agent for addressing triple-negative breast cancer (TNBC). Several factors have been considered for the optimization of the active targeted drug delivery system via the click-chemistry conjugation, as the impact of PEGylated surfactant that stabilize the NEs shell on conjugation efficiency, cytocompatibility with EMT6 cell line and colloidal stability over time of NEs. Results showed that a 660 Da PEG chain length contributed to NEs colloidal stability and had no impact on cell viability or on the antibody binding ability for its ligand after surface conjugation. Moreover, docetaxel was encapsulated into the oily core of NEs, with an encapsulation efficiency of 70 %. To validate our treatment strategy in vivo, the 4T1 murine breast cancer model was used. As a result, the comparison of active-targeted and non-targeted NEs revealed that only active-targeted NE could decrease the tumor growth rate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giovanna Lollo reports financial support and equipment, drugs, or supplies were provided by University Claude Bernard Lyon 1 - Campus Rockefeller. Benjamin Gibert reports financial support and equipment, drugs, or supplies were provided by Cancer Research Centre Lyon. Ilaria Marigo reports financial support and equipment, drugs, or supplies were provided by Veneto Oncology Institute. Patrick Mehlen declares to have a coflict of interest as shareholder of Netris Pharma. The other authors declare that they have no financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we have developed an innovative pH-triggered nanomedicine delivery system, targeting HER2-positive breast cancer cells for effective low-cost, imaging-guided drug delivery and precise therapy. The key feature of this system lies in its unique tumor interstitial fluid microenvironment-responsive drug release behavior which achieved tumor site-specific drug delivery. Our in vitro experiments demonstrated that the carbon dot-integrated material achieves more efficient DTX release (96.13 % at 72 h) in the tumor interstitial fluid microenvironment (pH 6.5), thereby boosting drug concentration at the tumor site and enhancing therapeutic efficacy. Further cell experiments confirmed the system's significant inhibitory effect on HER2-positive tumor cells SKBR3 in a pH 6.5 environment, and apoptosis assays indicating a notable increase in early cell apoptosis (from 8.39 % to 24.61 % compared with pH 7.4). Furthermore, the integration of HER2 aptamer within the carbon dot-based system enables targeted recognition and binding to tumor cells, ensuring more precise delivery of DTX while minimizing potential side effects. Crucially, the carbon dots in this system emit superior red fluorescence (the QY = 47.64 % excited at 535 nm compared with Rodamine 6G), enabling real-time visualization of the drug delivery process. This feature provides valuable feedback on treatment effectiveness, facilitating necessary adjustments. The small size (1.88 ± 0.48 nm) of carbon dots significantly improved their ability to penetrate biological barriers, while their low toxicity (no significant cell toxicity under 350 μg/mL) contributed to the formulation's outstanding biocompatibility. Overall, this carbon dot-enhanced drug delivery system offers immense potential for enhancing drug efficacy, minimizing side effects, and providing real-time treatment monitoring, thus proposing a innovate strategy for breast cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications. The liposomes were then characterized in terms of size, polydispersity index (PDI), docetaxel encapsulation rate and lamellarity. Antiproliferative activity was tested in human breast cancer models ranging from near-negative (MDA-MB-231), positive (MDA-MB-453) to HER2 positive. Pharmacokinetic studies were performed in C57BL/6 mice.Numerous batches of liposomes were synthesised using identical molar ratios and by varying the microfluidic parameters TFR, FRR and buffer. All synthesized liposomes have a size < 200 nm, but only Lipo-1, Lipo-6, Lipo-7, Lipo-8 have a PDI < 0.2, which meets our initial requirements. The size of the liposomes was correlated with the total FRR, for a 1:1 FRR the size is 122.2 ± 12.3 nm, whereas for a 1:3 FRR the size obtained is 163.4 ± 34.0 nm (p = 0.019. Three batches of liposomes were obtained with high docetaxel encapsulation rates > 80 %. Furthermore, in vitro studies on breast cancer cell lines demonstrated the efficacy of liposomes obtained by microfluidic mixing technique. These liposomes also showed improved pharmacokinetics compared to free docetaxel, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the immunoliposome, respectively).This suggests that switching to the microfluidic process will produce batches of liposomes with the same characteristics in terms of in vitro properties and efficacy, as well as the ability to release the encapsulated drug over time in vivo. This time-efficiency of the microfluidic technique is critical, especially in the early stages of development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mathilde Dacos reports administrative support was provided by Aix-Marseille University. Mathilde Dacos reports a relationship with Aix-Marseille University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC., Materials and Methods: In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints., Results: A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups., Conclusion: Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There are limitations in treating advanced prostate cancer (PC), especially castration-resistant (CR) cases, in renal transplant recipients (RTRs). We describe the case of RTR with metastatic CRPC (mCRPC) treated with docetaxel., Case Report: A 60-year-old man with end-stage renal disease due to autosomal-dominant polycystic kidney disease (ADPKD) underwent living-related kidney transplantation. A year later, he was diagnosed with PC (prostate-specific antigen level: 998 ng/mL). Prostate biopsy revealed prostatic adenocarcinoma with a Gleason score of 4 + 4 = 8. Radiographic examination revealed seminal vesicle invasion and multiple bone and lymph node metastases. Combined androgen blockade therapy was initiated; however, the patient was diagnosed with CRPC 6 months later. Triweekly docetaxel therapy was administered 28 months after diagnosis. The patient successfully completed 7 cycles of this therapy without major adverse events. However, after the 7th cycle, he developed a high fever caused by an infection of ADPKD-associated renal cysts. Therefore, docetaxel was discontinued, and enzalutamide was started, followed by abiraterone, but without any effect. We then introduced cabazitaxel but discontinued it because of hepatic dysfunction. Hence, the patient underwent a docetaxel rechallenge. He was administered the PEGylated form of the recombinant human granulocyte colony-stimulating factor for neutropenia prophylaxis. After 6 cycles of rechallenge docetaxel therapy, the patient accidentally fell, resulting in a cervical spine fracture and subsequent death due to respiratory failure., Conclusions: Docetaxel can be safely delivered to patients with CRPC after renal transplantation who are taking oral immunosuppressants. It can be a good treatment option for them., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Targeting critical pathways of cancer cells using combination drugs is gaining significant importance as drug resistance is lowered and drug efficacy is improved even at low concentrations. Docetaxel and 5-fluorouracil are chemotherapeutic drugs prescribed for patients with solid tumours. While coated polymeric nanoparticles can combat drug resistance by sequential release of drugs, this paper proposes to encapsulate docetaxel and 5-fluorouracil in chitosan nanoparticles. To further improve the solubility of chitosan nanoparticles, they are crosslinked with polyethylene glycol using formaldehyde as crosslinker. Various techniques were used to characterize the nanoparticles. HR-SEM images indicated the formation of nanoparticles, drug loading into the chitosan nanoparticles and crosslinking of polyethylene glycol to chitosan nanoparticles. The experimental strategies were designed to evaluate the synergistic combination of the drugs in nanoparticles against AGS cell lines. It was found that the drugs loaded in chitosan nanoparticles synergistically inhibited the cell viability of AGS cells with a combination effect at 0.414. The combined effect of the drugs was even more effective, with value at 0.23 in the case of polyethylene glycol crosslinked-drug-loaded chitosan nanoparticles. The DPPH scavenging activity of drugs encapsulated in polyethylene glycol crosslinked chitosan nanoparticles was more effective at 57.39% compared to drug-alone counter parts. To further confirm the synergistic efficacy of the drugs loaded in nanoparticles in inducing apoptosis, changes were observed using acridine orange /ethidium bromide staining. Results indicated that combination effect of drugs in nanoparticles was much higher in AGS cells when compared to drug-alone incubated groups. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiolabeled choline and PSMA PET have been largely tested in the initial staging of prostate cancer and for biochemical recurrence. Moreover, diverse data are now available about their role in the evaluation of response to local and systematic therapies, and their predictive impact on the prognosis, before and after therapy. Therefore, in the present systematic review, we aimed to describe the available data, to summarize the current evidence in these settings of disease. The aims of this systematic review were to (1) assess the utility of PSMA-PET and choline-PET in the assessment of response to systemic and local therapy, and to (2) determine the value of both tracers for the prediction of response to therapy and survival outcomes in prostate cancer. We performed a systematic literature search in PubMed/Scopus/Google Scholar/Cochrane/EMBASE databases (between January 2010 and October 2021) accordingly. The quality of the included studies was evaluated following the "Quality Assessment of Prognostic Accuracy Studies" tool (QUAPAS-2). We selected 40 articles: 23 articles discussed the use of PET imaging with [68Ga]PSMA-11 (16 articles/1123 patients) or [11C]/[18F]Choline (7 articles/356 patients) for the prediction of response to radiotherapy (RT) and survival outcomes. Seven articles (three with [68Ga]PSMA-11, three with [11C]Choline, one with [18F]Choline) assessed the role of PET imaging in the evaluation of response to docetaxel (as neoadjuvant therapy in one study, as first-line therapy in five studies, and as a palliative regimen in one study). Seven papers with radiolabeled [18F]Choline PET/CT (n = 121 patients) and three with [68Ga]PSMA-11 PET (n = 87 patients) were selected before and after enzalutamide/abiraterone acetate. Finally, [18F]Choline and [68Ga]PSMA-11 PET/CT as gatekeepers for the treatment of metastatic prostate cancer with Radium-223 were assessed in three papers. In conclusion, in patients undergoing RT, radiolabeled choline and [68Ga]PSMA-11 have an important prognostic role. In the case of systemic therapies, the role of such new-generation imaging techniques is still controversial without sufficient data, thus requiring additional in this scenario. [ABSTRACT FROM AUTHOR]

Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model (Mus musculus SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity. [ABSTRACT FROM AUTHOR]

In recent years, therapeutic drug monitoring (TDM) has been applied in docetaxel (DOC)-based anticancer therapy to precisely control various pharmacokinetic parameters, including the concentration of DOC in biofluids (e.g., plasma or urine), its clearance, and its area under the curve (AUC). The ability to determine these values and to monitor DOC levels in biological samples depends on the availability of precise and accurate analytical methods that both enable fast and sensitive analysis and can be implemented in routine clinical practice. This paper presents a new method for isolating DOC from plasma and urine samples based on the coupling of microextraction and advanced liquid chromatography with tandem mass spectrometry (LC-MS/MS). In the proposed method, biological samples are prepared via ultrasound-assisted dispersive liquid–liquid microextraction (UA-DLLME) using ethanol (EtOH) and chloroform (Chl) as the desorption and extraction solvents, respectively. The proposed protocol was fully validated according to the Food and Drug Administration (FDA) and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) requirements. The developed method was then applied to monitor the DOC profile in plasma and urine samples collected from a pediatric patient suffering from cardiac angiosarcoma (AS) with metastasis to lungs and mediastinal lymph nodes, who was receiving treatment with DOC at a dose of 30 mg/m2 body surface area. Due to the rarity of this disease, TDM was carried out to determine the exact levels of DOC at particular time points to ascertain which levels were conducive to maximizing the treatment's effectiveness while minimizing the drug's toxicity. To this end, the concentration-time profiles of DOC in the plasma and urine samples were determined, and the levels of DOC at specific time intervals up to 3 days after administration were measured. The results showed that DOC was present at higher concentrations in the plasma than in the urine samples, which is due to the fact that this drug is primarily metabolized in the liver and then eliminated with the bile. The obtained data provided information about the pharmacokinetic profile of DOC in pediatric patients with cardiac AS, which enabled the dose to be adjusted to achieve the optimal therapeutic regimen. The findings of this work demonstrate that the optimized method can be applied for the routine monitoring of DOC levels in plasma and urine samples as a part of pharmacotherapy in oncological patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most frequently diagnosed cancer in women, causing over 500,000 deaths worldwide. Human epidermal growth factor receptor 2 is overexpressed in roughly 15–20% of the breast cancer cases diagnosed nowadays, denoting poor prognoses. However, the presence of this receptor in tumoral cells provided patients with the opportunity for treatment with HER2 inhibitors, which have well-documented clinical benefits but still present variable grades of cardiotoxicity. We evaluated 22 patients, diagnosed with HER2-positive breast cancer, who underwent combination treatment with trastuzumab, pertuzumab and docetaxel, and we monitored their cardiac profiles through radionuclide ventriculography and cardiac-biomarker measurements both at the beginning of their treatment and after 6 months of therapy. Our results confirmed the good cardiac safety profile of this therapeutic scheme while also suggesting use of radionuclide ventriculography and dosing of NT-proBNP and ST2-IL33R for early detection of cardiac impairment. (1) Background: The aim of our study was to determine whether monitoring cardiac function through RNV and cardiac biomarkers could predict the cardiac impact of combined therapy with trastuzumab, pertuzumab and docetaxel, which are regularly used nowadays to treat HER2-positive breast cancer. (2) Methods: This prospective monocentric study included 22 patients, diagnosed with HER2-positive breast cancer, who had their LVEFs and cardiac biomarkers evaluated both at the beginning of their treatment and after 6 months. Among all of the enrolled patients, two blood specimens were collected to assess circulating cardiac biomarkers. RNV was performed in each patient after "in vivo" radiolabeling of the erythrocytes. The obtained results were then statistically correlated. (3) Results: The average LVEF decrease between the two time points was approximately 4%. Of the five biomarkers we considered in this paper, only NT-proBNP correlated with the LVEF values obtained both in the baseline study and after 6 months of follow-up (r = −0.615 for T0 and r = −0.751 for T1, respectively). ST2/IL-33R proved statistically significant at the T1 time point (r = −0.547). (4) Conclusions: A combination of LVEF, NT-proBNP and ST2/IL-33R assessment may be useful for early detection of cardiac impairment in breast cancer patients treated with trastuzumab, pertuzumab and docetaxel. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the leading causes of cancer deaths worldwide. The use of nanoparticles as radiosensitizers and drug delivery vehicles could open the door to solving many of the obstacles in current cancer treatments. Gold nanoparticles (GNPs) and docetaxel (DTX) have shown very promising synergetic radiosensitization effects, despite DTX toxicity to normal tissues. In this paper, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNPDTX-P) on GNP uptake in pancreatic cancer models in vitro and in vivo. The results show that LNPDTX-P-treated tumour samples have twice the amount of GNP uptake in both in vitro and in vivo models. These very promising results establish that LNPDTX-P have very similar outcomes to free DTX on tumour tissues. These results demonstrate the potential of incorporating GNPs and LNPDTX-P as radiosensitization tools to current radiotherapy protocols for improved tumour targeting. Current chemoradiation therapy suffers from normal tissue toxicity. Thus, we are proposing incorporating gold nanoparticles (GNPs) and docetaxel (DTX), as they have shown very promising synergetic radiosensitization effects. Here, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNPDTX-P) on GNP uptake in pancreatic cancer models in vitro and in vivo. For the in vitro experiment, a pancreatic cancer cell line, MIA PaCa-2, was cultured and dosed with 1 nM GNPs and 45 nM free DTX or an equivalent dose of LNPDTX-P. For the in vivo experiment, MIA PaCa-2 cells were implanted subcutaneously in NRG mice, and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or an equivalent dose of LNPDTX-P. The results show that LNPDTX-P-treated tumour samples had double the amount GNPs compared to control samples, both in vitro and in vivo. The results are very promising, as LNPDTX-P have superior targeting of tumour tissues compared to free DTX due to their nanosize and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX-P could be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Chemotherapy is widely used as a primary treatment or adjuvant therapy for cancer. Anti-microtubule agents (such as paclitaxel and docetaxel) are used for treating many types of cancer, either alone or in combination. However, their use has negative consequences that restrict the treatment's ability to continue. The principal negative effect is the so-called chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a complex ailment that depends on diversity in the mechanisms of action of the different chemotherapy drugs, which are not fully understood. In this paper, we review several neurophysiological and pathological characteristics, such as morphological changes, changes in ion channels, mitochondria and oxidative stress, cell death, changes in the immune response, and synaptic control, as well as the characteristics of neuropathic pain produced by paclitaxel. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurologic complication of chemotherapy, resulting in symptoms like pain, sensory loss, and numbness in the hands and feet that cause lots of uneasiness in patients with cancer. They often suffer from pain so severe that it interrupts the treatment, thus invalidating the entire chemotherapy-based healing process, and significantly reducing their quality of life. In this paper, we underline the role of the complement system in CIPN, highlighting the relevance of the C5a fragment and its receptor C5aR1, whose activation is thought to be involved in triggering a cascade of events that can lead to CIPN onset. Recent experimental data showed the ability of docetaxel and paclitaxel to specifically bind and activate C5aR1, thus shining light on one of the molecular mechanisms by which taxanes may activate a cascade of events leading to neuropathy. According to these new evidence, it was possible to suggest new mechanisms underlying the pathophysiology of CIPN. Hence, the C5a/C5aR1 axis may represent a new target for CIPN treatment, and the use of C5aR1 inhibitors can be proposed as a potential new therapeutic option to manage this high unmet medical need. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Nowadays, non-small cell lung cancer (NSCLC) is threatening the health of all mankind. Although many progresses on treatment of lung cancer have been achieved in the past few decades, the current treatment methods are still traditional surgery, radiotherapy, and chemotherapy, which had poor selectivity and side effects. Lower-toxicity and more efficient treatments are in sore need. In this paper, a smart nanodelivery platform based on photothermal therapy, chemotherapy, and immunotherapy was constructed. The nanoparticles are composed of novel photothermal agents, Mn-modified phthalocyanine derivative (MnIIIPC), docetaxel (DTX), and an effective targeting molecule, hyaluronic acid. The nanoplatform could release Mn2+ from MnIIIPC@DTX@ PLGA@Mn2+@HA(MDPMH) and probably activate tumor immunity through cGAS-STING and chemotherapy, respectively. Furthermore, DTX could be released in the process for removal of tumor cells. The "one-for-all" nanomaterial may shed some light on treating NSCLC in multiple methods. [ABSTRACT FROM AUTHOR]

Docetaxel could inhibit the proliferation of tumor cells by targeting microtubules. The extension of cellular microtubules plays an important role in the invasion and metastasis of tumor cells. This paper aims to study the distribution and mechanical properties of cytoskeletal proteins with low concentration of docetaxel. MTT assay was used to detect the minimum drug activity concentration of docetaxel on SKOV-3 cells, fluorescence staining was used to analyze the distribution of cytoskeleton proteins, scanning electron microscopy(SEM) was used to observe the morphology of single cells, and atomic force microscopy(AFM) was used to determine the microstructure and mechanical properties of cells. The results showed that the IC 10 of docetaxel was 1 ng/ml. Docetaxel can effectively inhibit the formation of cell pseudopodia, hinder the indirectness between cells, reduce the cell extension area, and make the cells malformed. In addition, when AFM analyzes the effects of drugs on cell microstructure and mechanical properties, the average cell surface roughness and cell height are positively correlated with the concentration of docetaxel. Especially when the concentration was 100 ng/ml, the adhesion decreased by 37.04% and Young's modulus increased by 1.57 times compared with the control group. This may be because docetaxel leads to microtubule remodeling and membrane protein aggregation, which affects cell microstructure and increases cell strength, leading to significant changes in the mechanical properties of ovarian cells. This is of great significance to the study of the formation mechanism of tumor cell invasion and migration activities mediated by actin., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release, anti-tumor activity toward α V β 3 -overexpressing A549 cells, blood circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7–8.3. Further studies indicated that t-M5DTX could effectively eradicate α V β 3 -overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. Nanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of α v β 3 overexpressing lung tumors. t-MDTX is further shown to effectively treat α v β 3 -positive patient-derived tumor models, lending it a high potential for clinical translation. [Display omitted] [ABSTRACT FROM AUTHOR]

The interactions between ligands and polymers are of great interest to drug delivery researches. In this work for the first time, Poly (lactic‐co‐glycolic acid) based polymers with arginine‐glycine‐aspartate (RGD) peptide ligands which are immediately self‐assembled into micellar nanoparticles (NPs) in contact with water have been investigated in the atomistic level. In this regard, the effect of polymer and RGD concentrations on the stability, size, interaction energies and other molecular properties of nanocarriers has been investigated using molecular dynamics simulation. In the next step, the microfluidic micellization and docetaxel (DTX) encapsulation has been simulated in comparison to bulk micellization. Results indicated that by employing only 20 wt % RGD‐conjugated polymer, the particles reach the stable properties and compactness without DTX. But, when the DTX was added, 30 wt.% of RGD‐conjugated polymers that assembled in microfluidic system is the best state nanocarrier for the smart target drug delivery for transfer of DTX drug into the Cancer cell. Comparisons of the results acquired in the current paper confirmed that engineering and tuning the self‐assembly in the interface of phases in microchennel resulted in a precise control on the particle size and resulted in the preparation of smaller and more stable NPs that can be exploited as ultra‐small, smart drug carriers. [ABSTRACT FROM AUTHOR]

Nowadays, non-small cell lung cancer (NSCLC) is threatening the health of all mankind. Although many progresses on treatment of lung cancer have been achieved in the past few decades, the current treatment methods are still traditional surgery, radiotherapy, and chemotherapy, which had poor selectivity and side effects. Lower-toxicity and more efficient treatments are in sore need. In this paper, a smart nanodelivery platform based on photothermal therapy, chemotherapy, and immunotherapy was constructed. The nanoparticles are composed of novel photothermal agents, Mn-modified phthalocyanine derivative (MnIIIPC), docetaxel (DTX), and an effective targeting molecule, hyaluronic acid. The nanoplatform could release Mn2+ from MnIIIPC@DTX@PLGA@Mn2+@HA(MDPMH) and probably activate tumor immunity through cGAS-STING and chemotherapy, respectively. Furthermore, DTX could be released in the process for removal of tumor cells. The "one-for-all" nanomaterial may shed some light on treating NSCLC in multiple methods. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to evaluate the derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma, as well as the survival benefits from induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU). The dNLR is an independent negative predictive factor for the disease. Patients with cTNM stage III disease and a low dNLR may benefit from induction chemotherapy. Background: This study aimed to evaluate the derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma (LAOSCC) and to assess the survival benefits from docetaxel, cisplatin, and 5-fluorouracil (5-FU) (TPF) induction chemotherapy (IC). Methods: Patients from a phase III trial involving TPF IC in stage III/IVA OSCC patients (NCT01542931) were enrolled. Receiver operating characteristic curves were constructed, and the area under the curve was computed to determine dNLR cutoff points. Kaplan–Meier survival estimates and Cox proportional hazards models were used for longitudinal analysis. Results: A total of 224 patients were identified (median age: 55.4 years; range: 26 to 75 years; median follow-up: 90 months; range: 3.2 to 93 months). The cutoff point for the dNLR was 1.555. Multivariate analysis showed that the dNLR was an independent negative predictive factor for survival (overall survival (OS): hazard ratio (HR) = 1.154, 95% confidence interval (CI): 1.018–1.309, p = 0.025; disease-free survival (DFS): HR = 1.123, 95% CI: 1.000–1.260, p = 0.050; local recurrence-free survival (LRFS): HR = 1.134, 95% CI: 1.002–1.283, p = 0.047; distant metastasis-free survival (DMFS): HR = 1.146, 95% CI: 1.010–1.300, p = 0.035). A low dNLR combined with cTNM stage III disease predicted benefit from TPF IC for the patients [OS (χ2 = 4.674, p = 0.031), DFS (χ2 = 7.134, p = 0.008), LRFS (χ2 = 5.937, p = 0.015), and DMFS (χ2 = 4.832, p = 0.028)]. Conclusions: The dNLR is an independent negative predictive factor in LAOSCC patients. Patients with cTNM stage III disease and a low dNLR can benefit from TPF IC. [ABSTRACT FROM AUTHOR]

Background: Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I–III, HER2-negative breast cancer. Methods: A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included. Results: TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98–1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89–1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16–1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC. Conclusions: Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases. [ABSTRACT FROM AUTHOR]

Background: To explore the role of GAB2 in pan-cancer based on bioinformatics analysis. Methods: Based on TCGA and GTEx databases, we used TIMER2.0 online analysis tool and R language to analyze the expression of GAB2 in pan-cancer. We used Kaplan–Meier Plotter to analyze the relationship between GAB2 and OS and RFS in pan-cancer. We utilized the CPTAC database to examine the expression of phosphorylated GAB2 in pan-cancer. We investigated the effects of mutation features on the occurrence and development of human cancers by cBioPortal and COSMIC. Using the database, we conducted an analysis of molecular compounds that have the potential to interact with GAB2 through molecular docking. Moreover, we use the TIMER to explore the relationship between GAB2 and immune cell infiltration, and draw relevant heatmaps by R language. Results: GAB2 was abnormally expressed in various tumors and was associated with prognosis. There were differences in the expression of GAB2 phosphorylation in tumor tissues and corresponding normal tissues among different types of tumors. GAB2 interacts with Docetaxel and was associated with immune cell infiltration in various tumors. Conclusion: GAB2 participates in regulating immune infiltration and affects the prognosis of patients. GAB2 may serve as a potential tumor marker. [ABSTRACT FROM AUTHOR]

Simple Summary: The prediction of tumor response after neoadjuvant FLOT therapy is highly necessary. The use of deep learning on gastroesophageal biopsies enabled us to extract predictive information. This prediction model could be easily applied in clinical decision making. Patients could avoid unnecessary treatment or receive an intensified FLOT therapy. Background: The aim of this study was to establish a deep learning prediction model for neoadjuvant FLOT chemotherapy response. The neural network utilized clinical data and visual information from whole-slide images (WSIs) of therapy-naïve gastroesophageal cancer biopsies. Methods: This study included 78 patients from the University Hospital of Cologne and 59 patients from the University Hospital of Heidelberg used as external validation. Results: After surgical resection, 33 patients from Cologne (42.3%) were ypN0 and 45 patients (57.7%) were ypN+, while 23 patients from Heidelberg (39.0%) were ypN0 and 36 patients (61.0%) were ypN+ (p = 0.695). The neural network had an accuracy of 92.1% to predict lymph node metastasis and the area under the curve (AUC) was 0.726. A total of 43 patients from Cologne (55.1%) had less than 50% residual vital tumor (RVT) compared to 34 patients from Heidelberg (57.6%, p = 0.955). The model was able to predict tumor regression with an error of ±14.1% and an AUC of 0.648. Conclusions: This study demonstrates that visual features extracted by deep learning from therapy-naïve biopsies of gastroesophageal adenocarcinomas correlate with positive lymph nodes and tumor regression. The results will be confirmed in prospective studies to achieve early allocation of patients to the most promising treatment. [ABSTRACT FROM AUTHOR]

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5–59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8–31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT. [ABSTRACT FROM AUTHOR]

Background/Aim: Androgen-independent prostate cancer (AIPC) is resistant to androgen-depletion therapy and is a recalcitrant disease. Docetaxel is the first-line treatment for AIPC, but has limited efficacy and severe side-effects. All cancers are methionine-addicted, which is termed the Hoffman effect. Recombinant methioninase (rMETase) targets methionine addiction. The purpose of the present study was to determine if the combination of docetaxel and rMETase is effective for AIPC. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of docetaxel and rMETase alone were determined for the human AIPC cell line PC-3 and Hs27 normal human fibroblasts in vitro. The synergistic efficacy for PC-3 and Hs27 using the combination of docetaxel and rMETase at their IC50s for PC-3 was determined. Results: The IC50 of docetaxel for PC-3 and for Hs27 was 0.72 nM and 0.94 nM, respectively. The IC50 of rMETase for PC-3 and for Hs27 was 0.67 U/ml and 0.76 U/ml, respectively. The combination of docetaxel and rMETase was synergistic for PC-3 but not Hs27 cells. Conclusion: The combination of a relatively low concentration of docetaxel and rMETase was synergistic and effective for AIPC. The present results also suggest that the effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity. The present results also suggest the future clinical potential of the combination of docetaxel and rMETase for AIPC. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle invasive bladder cancer (NMIBC) faces limitations in efficacy and significant side effects, aggravated by a recent global shortage. In this prospective clinical study, we report the outcomes of sequential intravesical administration of gemcitabine and docetaxel (Gem/Doce) as a first-line treatment for BCG-naïve patients with high-risk NMIBC (HR NMIBC). From October 2019 until April 2022, we enrolled 52 patients and followed the treatment protocol set forth by the University of Iowa. Follow-up assessments were conducted every 3 months. In this cohort, 25 (48.1%) patients were diagnosed with high-grade T1 (T1HG) bladder cancer, 10 (19.2%) patients had carcinoma in situ (CIS), and 17 (32.7%) patients had a combination of T1HG+CIS. The median time to first recurrence in the T1HG, CIS, and T1HG+CIS groups was 11, 10.5, and 8.8 months, respectively. The recurrence-free survival was 98.1%, 94.2%, and 80.8% at 6, 9, and 12 months, respectively. The rate of progression-free survival was 100%, 98.1%, and 92.3% at 6, 9, and 12 months, respectively. We demonstrated the safety and efficacy of Gem/Doce therapy in BCG-naïve patients with HR NMIBC during a one-year follow-up. Further research with extended follow-ups, as well as direct comparisons of Gem/Doce with other anticancer agents, is essential. [ABSTRACT FROM AUTHOR]

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system. While chemotherapy may initially be effective in patient with nasopharyngeal carcinoma (NPC), resistance often develops. Here, the authors identify PJA1 as a driver of resistance to docetaxel via inhibition of GSDME-mediated proptosis and target this using a PJA1 inhibitor to restore sensitivity in preclinical models of NPC. [ABSTRACT FROM AUTHOR]

Background: Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking. Methods: We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays. Results: Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor. Conclusions: The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC. [ABSTRACT FROM AUTHOR]

To investigate the clinical efficacy of epirubicin combined with docetaxel in postoperative patients with cervical cancer. A total of 124 postoperative cervical cancer patients were randomly allocated into two groups: the control group (n = 62) and the experimental group (n = 62), using a random number table. Patients in both groups underwent extensive hysterectomy, pelvic nerve-sparing lymphadenectomy, and other surgical interventions as deemed necessary. Postoperatively, the control group received intravenous epirubicin, while the experimental group received intravenous docetaxel in addition to epirubicin. After 3 courses of treatment, the serum levels of interleukin-2 (IL-2), IL-6, IL-4 and interferon (IFN-) in the experimental group were lower than that in the control group. The levels of IL-2/IL-6, IFN-/IL-4, IL-2/IL-4 and IFN-/IL-6 were lower than that in the control group. The serum levels of carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1) and squamous cell carcinoma antigen (SCC-Ag) were lower than that in the control group. The disease control rate was 74.19% (46/62), higher than 56.45% (35/62) in the control group. The incidence of adverse reactions was 6.45% (4/62), lower than 19.35% (12/62) in the control group. The combination of epirubicin and docetaxel demonstrates efficacy in the treatment of postoperative cervical cancer. [ABSTRACT FROM AUTHOR]

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients. [ABSTRACT FROM AUTHOR]

Prostate cancers represent a significant health problem, and their etiology is complex and multifaceted. It is estimated that in 2018, 1.3 million new cases and 359,000 deaths due to prostate cancer were diagnosed. They constitute the second most common group of cancers and the fifth most common cause of cancer-related deaths in men worldwide. The present study encompasses a literature review aimed at conducting an analysis of the potential of combined anticancer therapy as a prospective method for enhancing treatment efficacy, minimizing side effects, and improving long-term survival outcomes for prostate cancer patients. Combinations of compounds such as sunitinib with docetaxel, carboplatin with paclitaxel, estramustine or flutamide with luteinizing hormone-releasing hormone agonists, as well as docetaxel in conjunction with dexamethasone and octreotide, have demonstrated synergistic effects and an augmentation of therapeutic effectiveness. It is noteworthy to emphasize the potential enhancement of docetaxel's anticancer activity with concurrent administration of dexamethasone and octreotide, as well as combined therapy involving docetaxel, prednisone, and curcumin. [ABSTRACT FROM AUTHOR]

Background Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear. Methods Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively. Results The tpCR rate in the PLR− group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P  = .032). The tpCR rate in the NLR− group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P  = .024). The tpCR rate of the PLR−NLR− (PLR− and NLR−) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P  = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR− group (P  = .028 for EFS; P  = .047 for OS). Patients in the PLR−NLR− group had a longer EFS than those in the PLR+/NLR+ group (P  = .002). Conclusion PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) ranks as among the top two commonly diagnosed cancers in women worldwide. Triple-negative breast cancer (TNBC) is recognized globally as the most lethal subtype of BC, with patients often building resistance to conventional chemotherapy treatments. This study assesses the relationship between taxane-based chemotherapy resistance in BC and the oncoprotein epithelial membrane protein 2 (EMP2), with an emphasis on the aggressive TNBC group. Analyses of preclinical models and human tissue samples reveal that EMP2 may not only be used to predict patient response to taxanes but also serve as a therapeutic target for resistant disease. Our findings demonstrate a correlation between elevated EMP2 expression post-chemotherapy and reduced survival outcomes and reveal that targeting EMP2 in conjunction with chemotherapy yields a synergistic reduction in TNBC tumor volume. Thus, results shed light on a novel biomarker for guiding the personalized, targeted treatment of intractable and recurrent TNBC. Breast cancer (BC) remains among the most commonly diagnosed cancers in women worldwide. Triple-negative BC (TNBC) is a subset of BC characterized by aggressive behavior, a high risk of distant recurrence, and poor overall survival rates. Chemotherapy is the backbone for treatment in patients with TNBC, but outcomes remain poor compared to other BC subtypes, in part due to the lack of recognized functional targets. In this study, the expression of the tetraspan protein epithelial membrane protein 2 (EMP2) was explored as a predictor of TNBC response to standard chemotherapy. We demonstrate that EMP2 functions as a prognostic biomarker for patients treated with taxane-based chemotherapy, with high expression at both transcriptomic and protein levels following treatment correlating with poor overall survival. Moreover, we show that targeting EMP2 in combination with docetaxel reduces tumor load in syngeneic and xenograft models of TNBC. These results provide support for the prognostic and therapeutic potential of this tetraspan protein, suggesting that anti-EMP2 therapy may be beneficial for the treatment of select chemotherapy-resistant TNBC tumors. [ABSTRACT FROM AUTHOR]