Biology subjects

Quigley, D. A.

Publications and source records attributed to Quigley, D. A..

3 recordsLinked to original sources

bioRxiv2025

Genome-wide CRISPR screens identify PTGES3 as a novel AR modulator

The androgen receptor (AR) is a critical driver of prostate cancer (PCa). To study regulators of AR protein levels and oncogenic activity, we created the first live cell quantitative endogenous AR fluorescent reporters. Leveraging this novel AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators including HOXB13 and GATA2 and also unexpected top hits including PTGES3, a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell cycle arrest, and cell death in AR-driven PCa models. PTGES3 is not a commonly essential gene, and our data nominate it as a prime PCa therapeutic target. Clinically, analysis of PCa data demonstrate that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, forms a protein complex with AR in the nucleus, regulates AR protein stability in vitro and in vivo and modulates AR function in the nucleus at AR target genes. PTGES3 represents a novel therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.

cancer biology↗

bioRxiv2024

A prostate cancer gastrointestinal transcriptional phenotype may be associated with diminished response to AR-targeted therapy

BackgroundProstate cancer is a heterogenous disease, but once it becomes metastatic it eventually becomes treatment resistant. One mechanism of resistance to AR-targeting therapy is lineage plasticity, where the tumor undergoes a transformation to an AR-indifferent phenotype, most studied in the context of neuroendocrine prostate cancer (NEPC). However, activation of additional de- or trans-differentiation programs, including a gastrointestinal (GI) gene expression program, has been suggested as an alternative method of resistance. In this study, we explored the previously identified GI prostate cancer phenotype (PCa-GI) in a large cohort of metastatic castration-resistant prostate cancer (mCRPC) patient biopsy samples. MethodsWe analyzed a dataset of 634 mCRPC samples with batch effect corrected gene expression data from the West Coast Dream Team (WCDT), the East Coast Dream Team (ECDT), the Fred Hutchinson Cancer Research Center (FHCRC) and the Weill Cornell Medical center (WCM). Survival data was available from the WCDT and ECDT cohorts. We calculated a gene expression GI score using the sum of z-scores of genes from a published set of PCa-GI-defining genes (N=38). Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards regression with endpoint overall survival from time of biopsy to death of any cause. ResultsWe found that the PCa-GI score had a bimodal distribution, identifying a distinct set of tumors with an activated GI expression pattern. Approximately 35% of samples were classified as PCa-GI high, which was concordant with prior reports. Liver metastases had the highest median score but after excluding liver samples, 29% of the remaining samples were still classified as PCa-GI high, suggesting a distinct phenotype not exclusive to liver metastases. No correlation was observed between GI score and proliferation, AR signaling, or NEPC scores. Furthermore, the PCa-GI score was not associated with genomic alterations in AR, FOXA1, RB1, TP53 or PTEN. However, tumors with MYC amplifications showed significantly higher GI scores (p=0.0001). Patients with PCa-GI tumors had a shorter survival (HR=1.5 [1.1-2.1], p=0.02), but this result was not significant after adjusting for the liver as metastatic site (HR=1.2 [0.82-1.7], p=0.35). Patients with PCa-GI low samples had a better outcome after androgen receptor signaling inhibitors (ASI, abiraterone or enzalutamide) than other therapies (HR=0.37 [0.22-0.61], p=0.0001) while the benefit of ASI was smaller and non-significant for PCa-GI high samples (HR=0.55 [0.29-1.1], p=0.07). A differential pathway analysis identified FOXA2 signaling to be upregulated PCa-GI high tumors (FDR = 3.7 x 10-13). ConclusionsThe PCa-GI phenotype is prevalent in clinical mCRPC samples and may represent a distinct biological entity. PCa-GI tumors may respond less to ASI and could offer a strategy to study novel therapeutic targets.

cancer biology↗

bioRxiv2020

Autoantibody landscape of advanced prostate cancer

Although the importance of T-cell immune responses is well appreciated in cancer, autoantibody responses are less well-characterized. Nevertheless, autoantibody responses are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. We performed serum epitope repertoire analysis (SERA) on a total of 1,229 serum samples obtained from a cohort of 72 men with metastatic castration-resistant prostate cancer (mCRPC) and 1,157 healthy control patients to characterize the autoantibody landscape of mCRPC. Using whole-genome sequencing results from paired solid-tumor metastasis biopsies and germline specimens, we identified tumor-specific epitopes in 29 mutant and 11 non-mutant proteins. Autoantibody enrichments for the top candidate autoantigen (NY-ESO-1) were validated using ELISA performed on the prostate cancer cohort and an independent cohort of 106 patients with melanoma. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest in advanced prostate cancer. Statement of significanceAutoantibodies have been shown to inform treatment response and candidate drug targets in various cancers. We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new next-generation sequencing-based approach to antibody profiling to reveal novel cancer-specific antigens and epitopes. Disclosure of Potential Conflicts of InterestJJA reports receiving consulting income from Janssen Biotech and Merck and honoraria from Astellas for speakers fees. MR reports receiving commercial research support from Novartis, Johnson & Johnson, Merck, Astellas, and Medivation, and is a consultant/advisory board member for Constellation Pharmaceuticals, Amgen, Ambrx, Johnson & Johnson, and Bayer. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Dynavax, Genentech, Merck, Nektar, Novartis, Roche and Sanofi, is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, RAPT, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics. FYF serves on the advisory board for Dendreon, EMD Serono, Janssen Oncology, Ferring, Sanofi, Blue Earth Diagnostics, Celgene, consults for Bayer, Medivation/Astellas, Genetech, and Nutcracker Therapeutics, has honoraria from Clovis Oncology, and is a founder and has an ownership stake in PFS Genomics. SGZ and FYF have patent applications with Decipher Biosciences. SGZ and FYF have a patent application licensed to PFS Genomics. SGZ and FYF have patent applications with Celgene. WAH, RW, KK, PSD, and JCS have ownership of stocks or shares at Serimmune, paid employment at Serimmune, board membership at Serimmune, and patent applications on behalf of Serimmune.

cancer biology↗