Publications by authors named "George Seed"
Article Synopsis
- - 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.
View Article and Find Full Text PDFInflammation 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.
View Article and Find Full Text PDFArticle 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.
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).
Article Synopsis
- - 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
- CD38 is an ectoenzyme that contributes to the production of adenosine, which plays a role in how tumors evade the immune system, particularly in prostate cancer.* -
- The study aimed to analyze CD38 expression in prostate cancer cells and immune cells, using samples from multiple patient cohorts to link this expression to clinical outcomes.* -
- Findings showed that higher CD38 mRNA levels in metastatic castration-resistant prostate cancer (mCRPC) were linked to activated immune signaling pathways, specifically involving certain interleukins.*
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.
Article Synopsis
- 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.
Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression.
Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS).
Background: Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue.
Methods: Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies.
Background: Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.
Methods: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures.
Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency. We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity. Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.
View Article and Find Full Text PDFdeletions and mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of -deleted/-mutated metastatic CRPC (mCRPC). We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC.
View Article and Find Full Text PDFPersistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.
View Article and Find Full Text PDFArticle Synopsis
- * The study analyzed blood samples from 571 mCRPC patients in two clinical trials, examining the relationship between cfDNA levels and patient outcomes such as prostate-specific antigen (PSA) response, radiological progression-free survival (rPFS), and overall survival (OS).
- * Results indicated that higher baseline cfDNA concentrations correlated with poorer rPFS and OS, making cfDNA an independent prognostic factor, while declines in cfDNA levels during treatment were associated with positive PSA responses; however, the study faced some limitations.