A5067036938- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Prostate Cancer Diagnosis and Treatment
- Immunotherapy and Immune Responses
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- Cancer Immunotherapy and Biomarkers
- Tannin, Tannase and Anticancer Activities
- Mechanisms of cancer metastasis
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Glutathione Transferases and Polymorphisms
- Kruppel-like factors research
- Cancer, Hypoxia, and Metabolism
- Lung Cancer Research Studies
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Advanced Proteomics Techniques and Applications
- Estrogen and related hormone effects
- CRISPR and Genetic Engineering
- Receptor Mechanisms and Signaling
- Cancer-related molecular mechanisms research
- PARP inhibition in cancer therapy
- Genetic factors in colorectal cancer
UCSF Helen Diller Family Comprehensive Cancer Center
2013-2025
University of California, San Francisco
2016-2025
University of California, Santa Cruz
2018
University of California, Los Angeles
2018
University of British Columbia
2017
Tampere University
2017
BC Cancer Agency
2017
Oregon Health & Science University
2017
University of California, Davis
2017
Duke University
2009
Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era modern androgen receptor (AR)-targeting therapy. We sought to characterize clinical genomic t-SCNC a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant (mCRPC) underwent tumor biopsy were followed for survival. Metastatic specimens independent, blinded pathology review along RNA/DNA...
Background: Real-time knowledge of the somatic genome can influence management patients with metastatic castration-resistant prostate cancer (mCRPC). While routine tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample genome. However, no systematic comparisons matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling replace need for direct sampling. Methods: We targeted sequencing...
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination (HRR) such as
Significance The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with metastatic castration-resistant prostate cancer. However, not all patients respond, and de novo resistance mechanisms are largely unknown. To clarify that contribute to resistance, we conducted a single-arm clinical trial. Metastatic tissue biopsies were required prior study entry so could attempt identify molecular features associated resistance. Transcriptional profiling...
Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis inevitable. Thus, there an urgent need to develop more effective treatments beyond hormonal manipulation. We sought identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with goal of identifying candidate rapid translation into proof concept Phase II trials mCRPC. To evidence activation druggable these patients,...
Analysis of DNA methylation is a valuable tool to understand disease progression and increasingly being used create diagnostic prognostic clinical biomarkers. While conversion cytosine 5-methylcytosine (5mC) commonly results in transcriptional repression, further 5-hydroxymethylcytosine (5hmC) associated with activation. Here we perform the first study integrating whole-genome 5hmC DNA, 5mC, transcriptome sequencing samples benign, localized, advanced prostate cancer. shown mark activation...
Abstract Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation and second-generation receptor (AR)–targeted selectively favor the development of treatment-resistant subtypes metastatic castration-resistant (mCRPC), defined by AR neuroendocrine (NE) markers. Molecular drivers double-negative (AR−/NE−) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent integrating matched RNA sequencing,...
Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired after progression, multiple samples from the same individual. t-SCNC was significantly less likely to have amplification AR or an intergenic AR-enhancer locus, demonstrated lower...
Abstract The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which tumors manifest reduced dependency on AR. To improve our understanding resistance, herein we analyze transcriptomes matched biopsies from men with CRPC obtained prior to treatment and at progression ( n = 21)....
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of cancer. mCRPC receptor (AR) inhibitors by amplifying AR signaling or evolving into therapy-resistant subtypes do not depend on AR. Elucidation epigenetic underpinnings these could provide important insights drivers resistance. In this study, we produced chromatin accessibility maps linked to binding lineage-specific transcription factors (TF)...
Abstract The impact of variations in the three-dimensional structure genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, bisulfite 5-hydroxymethylcytosine (5hmC) and RNA across a cohort 80 biopsy samples from patients metastatic castration-resistant prostate cancer. Dramatic differences were present gene expression, 5-methylcytosine/5hmC methylation structural variation versus...
Loss of PTEN and activation phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition mammalian target rapamycin (mTOR), a downstream signaling, results cell cycle arrest apoptosis multiple vitro vivo models However, single-agent use mTOR inhibition has limited clinical success, the identification molecular events mitigating tumor response to remains critical question. Here, using genetically engineered human epithelial cells (PrEC), we show that MYC, frequent...
To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely affect diagnostic yields.This study was institutional review board approved, written informed consent obtained. In a phase II trial assessing response everolimus, 31 mCRPC underwent 54 procedures (eight before 23 both during treatment). Variables assessed...
5003 Background: Mechanisms of resistance to androgen signaling inhibitors such as Abi or Enz are poorly understood. An increasing % these pts develop NEPC. Pathologic (path), clinical, and genomic characterization with NEPC was undertaken in the context WCDT project, which seeks identify genetic pathways underlying primary acquired Enz. Methods: Eligible mCRPC underwent a metastasis (met) biopsy (bx) at one 5 centers, using standardized bx protocol, were uniformly followed for clinical...
Luminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct clinically important in predicting response therapy. These not described metastatic cancer.To identify clinical molecular correlates luminal castration-resistant (mCRPC) investigate differences survival, particularly after treatment with androgen-signaling inhibitors (ASIs).In this cohort study, a retrospective analysis was conducted 4 cohorts mCRPC (N = 634) across multiple academic centers....
<p>Supplementary Figure 4 shows a co-culture of tumor-antigen specific T cell mediated killing tumor cells +/- AR inhibition or MHCI inhibition.</p>
<p>Supplementary Figure 3 shows validation of AR binding in MHC regulatory genes interest +/- inhibition with enzalutamide.</p>
<div>Abstract<p>Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as model to examine how androgen-dependent tumors undergo evasion downregulation the major histocompatibility complex class I (MHCI). We report that response immunotherapy in late-stage is associated with elevated MHC expression. To uncover mechanism, performed genome-wide CRISPR interference (CRISPRi) screen identified androgen receptor...
<p>Supplementary Figure 5 provides <i>in vivo</i> validation of enhanced T cell responses and tumor control after AR knockdown.</p>
<p>Supplementary Figure 7 is a graphical abstract of how AR regulates MHCI expression in prostate tumor cells.</p>