Publications by authors named "Bertan C"
Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need.
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- - PARP inhibitors show promise in treating castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects, but the reasons behind resistance are not completely understood.
- - A study from the TOPARP-B trial found that 79% of BRCA2/PALB2-mutated tumors exhibited reversion mutations at the end of treatment, with many related to POLQ-mediated DNA repair mechanisms.
- - In cases of BRCA2 homozygous deletions, rare subclones lacking the BRCA2 deletion are selected for after PARP inhibitor treatment, indicating the necessity for restored HRR function in developing resistance.
Article Synopsis
- * BCL2, an anti-apoptotic protein, is upregulated in these aggressive prostate cancers, which presents a potential target for therapy and highlights the importance of studying its expression in metastatic CRPC (mCRPC).
- * Research shows that BCL2 is more prevalent in AR-negative mCRPC and is linked to poorer survival outcomes; also, its regulation involves DNA methylation and a transcription factor called ASCL1, suggesting the need for combination therapies to improve treatment efficacy.
BACKGROUNDClinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome, and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial.
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- The study investigates the effectiveness of the AKT inhibitor capivasertib when combined with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who did not respond well to prior treatments with abiraterone acetate and docetaxel.
- Conducted as a double-blind, randomized phase 2 trial with 100 men, the primary focus was on the composite response rate, which showed no significant improvement with the combination treatment compared to placebo.
- Analysis revealed that patients with PTEN loss had poorer overall survival regardless of treatment, with common side effects including diarrhea and fatigue, indicating that while the combination was tolerable, it did not enhance treatment outcomes.
Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear.
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- Germline mutations in the ATM gene, found in 0.5-1% of the population, are linked to a higher risk of aggressive prostate cancer (PC), but their clinical features are not well understood.
- This study focused on patients with advanced metastatic castration-resistant prostate cancer (CRPC) who had these mutations identified through initial tumor DNA sequencing, collecting data on demographic details, family history, and clinical outcomes.
- Among the seven identified patients (0.6%), most had a family history of various cancers, with a median overall survival from diagnosis of 7.1 years, indicating that the presence of these mutations could be significant in understanding PC progression and patient outcomes.
Article Synopsis
- B7-H3 is a key protein found on the surface of prostate cancer cells, particularly in castration-resistant prostate cancer (CRPC), and its role in cancer therapy is being studied to help target treatments more effectively.
- Researchers analyzed samples from 98 prostate cancer patients, comparing hormone-sensitive and castration-resistant biopsies to evaluate B7-H3 expression and link it to genomic data.
- The study found that B7-H3 is highly expressed in the majority of CRPC cases and remained stable during the transition from hormone-sensitive to castration-resistant stages, indicating its potential as a target for antibody-drug conjugate therapies.
Article Synopsis
- - The study evaluated the combined effects of guadecitabine and pembrolizumab on patients with advanced solid tumors, aiming to see if guadecitabine can make tumors more sensitive to pembrolizumab, which targets immune checkpoints.
- - In a phase 1 trial with 34 participants, the recommended dosage was established as guadecitabine 30 mg/m on specific days alongside pembrolizumab; common side effects included neutropenia and fatigue, but there were no treatment-related deaths reported.
- - Preliminary results showed a 7% objective response rate and 37% of patients achieved disease control for 24 weeks or more; notably, a significant reduction in DNA methylation was observed in
Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited.
Objective: To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC and to determine their association with overall survival (OS).
The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC).
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- - Researchers found that HER3, a protein often overexpressed in aggressive prostate cancer, is linked to faster progression to castration resistance and lower survival rates.
- - The study identified that NRG1, a ligand for HER3, is primarily produced by certain immune cells in the tumor environment, and its presence promotes cancer cell growth.
- - Targeting HER3 with specific therapies, like the antibody-drug conjugate U3-1402, shows promise in fighting HER3-positive prostate cancer, suggesting the need for further clinical trials.
Article Synopsis
- Better blood tests are needed for metastatic castration-resistant prostate cancer (mCRPC) to guide treatment decisions, and low-pass whole-genome sequencing (lpWGS) of circulating tumor DNA (ctDNA) shows promise in providing insights into mCRPC behavior.
- The study examined plasma lpWGS data from 188 mCRPC patients undergoing two phase 3 clinical trials, with an aim to assess its prognostic value and its ability to correlate with treatment response.
- Findings suggest that plasma tumor fraction is a strong predictor of overall survival and is more informative than existing biomarkers, while genomic instability indicated by large-scale transition scores was linked to previous treatments but not to others like taxane or radiation therapy.*
Article Synopsis
- * The TOPARP-B phase II clinical trial showed that APC patients with homozygous deletions benefit the most from olaparib treatment, especially those with biallelic mutations.
- * Loss of ATM protein is linked to improved outcomes, and RAD51 foci loss helps identify tumors with specific genetic alterations that respond well to PARP inhibition.
Article Synopsis
- Early-phase cancer clinical trials are increasingly available for advanced cancer patients who have few treatment options left, often requiring research tissue biopsies.
- An audit over two years showed that ultrasound-guided research biopsies were safe, yielded sufficient tumor samples, and revealed actionable mutations in 30% of cases tested with next-generation sequencing.
- Despite these benefits, the direct advantages of the research biopsies were limited to a minority of patients, highlighting the need for clear and informed consent in these procedures.
Article Synopsis
- The study investigates the role of ATM (Ataxia Telangiectasia Mutated) gene alterations in metastatic prostate cancer, revealing that about 11% of patients show ATM loss in biopsies, which is often linked to genomic instability.
- Researchers utilized advanced techniques like immunohistochemistry and next-generation sequencing to analyze cancer biopsies and created modified cell models to test drug responses, finding that ATM-deficient cancers respond variably to PARP inhibitors but exhibit better results with combined ATR and PARP inhibition.
- Despite ATM loss not correlating with worse clinical outcomes, it signifies a distinct and potentially targetable subtype of aggressive prostate cancer, emphasizing the need for tailored treatment strategies.
Purpose: Cyclin-dependent kinase 12 (CDK12) aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte (TIL) data.
Experimental Design: Patients with mCRPC consented to the molecular analyses of diagnostic and mCRPC biopsies.
Background: In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.
View Article and Find Full Text PDFBackground: This case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.
Case Presentation: A 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved.
Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.
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- The study investigates the genomic differences between primary prostate cancer and metastatic castration-resistant prostate cancer (mCRPC), analyzing biopsies from patients who developed mCRPC.
- Researchers examined 470 treatment-naive prostate cancer biopsies and 61 matched mCRPC biopsies, utilizing targeted and low-pass whole-genome sequencing to identify common mutations and copy number variations.
- Key findings include higher than previously reported mutations in TP53, BRCA2, and CDK12, and the discovery that RB1 loss in primary tumors correlates with poorer patient prognosis, indicating significant genomic differences between early-stage and more advanced cancer.
Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.
Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals.
Background: Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility.
Objective: To elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR).
Design, Setting, And Participants: Membranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data.