Abstract 1718: The importance of clinically relevant rapid autopsy specimens and LuCaP patient-derived xenograft models to interrogate the heterogeneous and evolving treatment resistance of castration-resistant prostate cancer

2015 ◽  
Author(s):  
Colm Morrissey ◽  
Ming H. Lam ◽  
Tia S. Higano ◽  
Lawrence D. True ◽  
Martine Roudier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Patient Derived Xenograft ◽  
Xenograft Models ◽  
Autopsy Specimens ◽  
Rapid Autopsy

scholarly journals Frequent discordance betweenERGgene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer

The Prostate ◽  
2014 ◽  
Vol 74 (12) ◽  
pp. 1199-1208 ◽  
Author(s):  
Aaron M. Udager ◽  
Yang Shi ◽  
Scott A. Tomlins ◽  
Ajjai Alva ◽  
Javed Siddiqui ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Rapid Autopsy

scholarly journals Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

2019 ◽  
Vol 26 (1) ◽  
pp. R31-R52 ◽  
Author(s):  
Simon Linder ◽  
Henk G van der Poel ◽  
Andries M Bergman ◽  
Wilbert Zwart ◽  
Stefan Prekovic
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Advanced Prostate Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Castration Resistant ◽  
Novel Drugs

The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

scholarly journals Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1167-1179
Author(s):  
David R. Wise ◽  
Jeffrey A. Schneider ◽  
Joshua Armenia ◽  
Victor Adorno Febles ◽  
Bridget McLaughlin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Nk Cells ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dkk1 Expression ◽  
Rapid Autopsy ◽  
Dickkopf 1

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

scholarly journals Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madonna R. Peter ◽  
Misha Bilenky ◽  
Alastair Davies ◽  
Ruth Isserlin ◽  
Gary D. Bader ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Disease ◽  
Xenograft Model ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Treatment Target ◽  
Castration Resistant ◽  
Genome Wide ◽  
Methylation Patterns

AbstractAndrogens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.

scholarly journals Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Nature ◽  
2021 ◽  
Author(s):  
Lanbo Xiao ◽  
Abhijit Parolia ◽  
Yuanyuan Qiao ◽  
Pushpinder Bawa ◽  
Sanjana Eyunni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Regulatory Elements ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Super Enhancer ◽  
Potent Inhibition ◽  
Promising Therapeutic Approach ◽  
Atpase Subunits ◽  
Xenograft Models

AbstractThe switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

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