Adam Sharp
A5069346188- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Estrogen and related hormone effects
- Hormonal and reproductive studies
- Radiopharmaceutical Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Immunotherapy and Immune Responses
- PARP inhibition in cancer therapy
- Cell Adhesion Molecules Research
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Ubiquitin and proteasome pathways
- Molecular Biology Techniques and Applications
- Prostate Cancer Diagnosis and Treatment
- Mass Spectrometry Techniques and Applications
- Eicosanoids and Hypertension Pharmacology
- Computational Drug Discovery Methods
- Cancer Research and Treatments
- Cholesterol and Lipid Metabolism
- Monoclonal and Polyclonal Antibodies Research
- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- Heat shock proteins research
- Synthesis and biological activity
Institute of Cancer Research
2016-2025
Royal Marsden Hospital
2016-2024
Cancer Research UK
2003-2024
Royal Marsden NHS Foundation Trust
2015-2024
Binghamton University
2023
Kaiser Permanente
2023
Weatherford College
2023
Cordoba University
2023
Institute of Cancer Research
2022-2023
Stanford University
2022
Abstract Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. now report targeted and whole-exome sequencing serial circulating cell-free (cfDNA) samples collected during this trial. Decreases cfDNA concentration independently associated outcome multivariable analyses (HR overall...
Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility. To elucidate PC PSMA and associate this with defective DNA damage repair (DDR). Membranous (mPSMA) was scored immunohistochemically from metastatic castration-resistant (mCRPC) matching, same-patient, diagnostic biopsies, correlated next-generation sequencing (NGS) clinical outcome data. Expression of mPSMA quantitated by modified H-score. Patient tested NGS. Gene activity...
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 (PC) tissue.Following generation validation of a potentially novel antibody for IHC, protein was determined 358 primary samples 293 metastatic biopsies. Associations disease...
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor conserved bromodomain. We...
BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.
Abstract Inflammation is a hallmark of cancer 1 . In patients with cancer, peripheral blood myeloid expansion, indicated by high neutrophil-to-lymphocyte ratio, associates shorter survival and treatment resistance across malignancies therapeutic modalities 2–5 Whether inflammation drives progression prostate in humans remain unclear. Here we show that inhibition chemotaxis can reduce tumour-elicited reverse therapy subset metastatic castration-resistant (CRPC). We higher ratio reflects...
Abstract Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies overcome this are urgently required. We evaluated how bromodomain extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR in CRPC. Experimental Design: determined associations between BET expression, AR-driven transcription, patient outcome; the effect mechanism by which chemical BETi (JQ1...
Abstract Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported castration-resistant (CRPC). We monitored expression during disease progression assessed the molecular clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC). Experimental Design: identified 89 patients mCRPC who had hormone-naive tumor samples available: These were analyzed for CHD1, PTEN, ERG by IHC. status was determined targeted next-generation...
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone enzalutamide.To develop a validated assay for detection AR-V7 protein tumour tissue determine its expression clinical significance as patients progress from hormone-sensitive (HSPC) CRPC.Following monoclonal antibody generation validation, we retrospectively identified who had HSPC CRPC available immunohistochemical (IHC)...
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones regulate gene expression. Pharmacological inhibition by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show is essential for repair DNA double-strand breaks (DSBs) mediates formation oncogenic rearrangements engaging non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide are associated with enhanced acetylation...
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple models identified CXCR7, an atypical chemokine receptor, as one most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding enhancer 110 kb downstream gene and expression was restored upon deprivation. We demonstrate critical regulator sensitivity required for...
Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some loss PCs respond. To characterise ATM-deficient lethal PC and to study synthetic therapeutic strategies for subset. We studied advanced biopsies using validated immunohistochemical (IHC) next-generation sequencing (NGS) assays. In vitro cell line models modified CRISPR-Cas9 impair function were generated used drug-sensitivity functional assays,...
Abstract Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by low frequency. Experimental Design: We evaluated liquid biopsies apheresis to increase CTC yield from patients suffering metastatic prostate cancer, allow precise gene copy-number calls, and disease heterogeneity. Results: Apheresis was well tolerated allowed the separation of large numbers CTCs; average 7.5 mL peripheral blood 167 CTCs, whereas per (mean volume: 59.5 mL) 12,546...
Activation of the PI3K/AKT/mTOR pathway through loss phosphatase and tensin homolog (PTEN) occurs in approximately 50% patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition androgen receptor (AR) AKT may be beneficial mCRPC PTEN loss.
B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development patient selection for targeted therapies.To characterise same-patient hormone-sensitive (HSPC) castration-resistant (CRPC) PC biopsies, associating this genomics, evaluate antitumour activity an anti-B7-H3 antibody-drug conjugate (ADC) human CRPC vitro...
Abstract Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This the first report of ongoing Phase 1/2a PETRA (NCT04644068) trial. Methods: Pts advanced breast, ovarian, prostate or pancreatic cancer bearing germline somatic BRCA1/2, PALB2 RAD51C/D mutations received QD PO until disease progression. ECOG PS 0-2 Hb ≥9.0 g/dL were required. Prior...
Abstract Prostate cancer is the most common in men and it estimated that over 350,000 worldwide die of prostate every year. There remains an unmet clinical need to improve how clinically significant diagnosed develop new treatments for advanced disease. Aberrant glycosylation a hallmark implicated tumour growth, metastasis, immune evasion. One key drivers aberrant dysregulated expression enzymes within cell. Here, we demonstrate using multiple independent cohorts glycosyltransferase enzyme...
Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of cancers homologous recombination DNA (HRD) repair defects, and such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition platinum, has increased interest in the utilisation these drugs against subset diseases. Here we report three patients castration-resistant PCa HRD defects having exceptional responses...
Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons CTC counts and biopsy AR-V7 protein expression. To determine the reproducibility AdnaTest testing, associations clinical characteristics, CellSearch counts, expression overall survival (OS). status was determined for 227 peripheral blood samples, from 181 mCRPC...
Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced 'castrate-resistant' disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity lethal disease, hormone-responsive and -resistant PC cells expressing luciferase-based reporter were transfected with miR inhibitor library; 78 inhibitors significantly altered activity. Upon validation, miR-346, miR-361-3p miR-197 markedly reduced transcriptional activity, mRNA protein levels,...