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 Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Epigenomics ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1317-1332
Author(s):  
Madonna R Peter ◽  
Misha Bilenky ◽  
Ruth Isserlin ◽  
Gary D Bader ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Cell Free Dna ◽  
Targeting Therapy ◽  
Castration Resistant ◽  
Free Dna ◽  
Aggressive Form ◽  
Genome Wide

Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Patients & methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression. Importantly, we also report that markers associated with a highly aggressive form of the disease, neuroendocrine-CRPC, were associated with a faster time to clinical progression. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

scholarly journals Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

2020 ◽  
Author(s):  
Madonna R. Peter ◽  
Misha Bilenky ◽  
Ruth Isserlin ◽  
Gary D. Bader ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Cell Free Dna ◽  
Targeting Therapy ◽  
Castration Resistant ◽  
Free Dna ◽  
Aggressive Form ◽  
Genome Wide

AbstractAimWe examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment.Materials and MethodsGenome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed.ResultsAlterations in methylation states previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression (TTP). Importantly, we also report that markers associated with a highly aggressive form of the disease, Neuroendocrine-CRPC, were associated with a faster TTP.ConclusionOur findings highlight the potential of monitoring cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

Comparison of enzalutamide and bicalutamide in patients with non-metastatic castration-resistant prostate cancer: Number needed to treat to achieve one additional patient free of clinical progression events.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 228-228
Author(s):  
Lawrence Ivan Karsh ◽  
David F. Penson ◽  
Raoul Concepcion ◽  
Scott Flanders ◽  
Bruce A. Brown ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Absolute Risk ◽  
Specific Antigen ◽  
Additional Patient ◽  
Number Needed To Treat ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Free Psa ◽  
Castration Resistant ◽  
Psa Progression

228 Background: Androgen receptor inhibitors enzalutamide (ENZA) and bicalutamide (BIC) are used to treat metastatic castration-resistant prostate cancer (mCRPC). The Phase 2 STRIVE trial included 35% non-metastatic (m0) and 65% metastatic CRPC patients (pts); ENZA reduced the risk of progression or death among pts, with an adverse event profile consistent with previous trials. The objective of this analysis was to compare ENZA with BIC using the number needed to treat (NNT) to achieve one additional pt with m0CRPC, with either a progression-free survival (PFS) event, radiographic PFS (rPFS), or free of prostate-specific antigen (PSA) progression at 1 year and 2 years. Methods: The 1- and 2-year event rates of PFS, rPFS, and progression-free PSA among pts treated with ENZA and BIC were obtained from the STRIVE trial report. The NNT was calculated as the reciprocal of the absolute risk reduction between ENZA and BIC at each time point. This represents the number of pts that need to be treated with ENZA, compared with BIC, to obtain one additional pt free of a clinical progression event. PFS was defined as the time from randomization to investigator-assessed radiographic (bone or soft tissue) progression, PSA progression, or death. The 95% confidence interval (CI) of the NNT was derived based on the 95% CI of the event rate difference. Results: The NNT to achieve one additional pt with PFS at 1 year, comparing ENZA with BIC, was 2.2 (95% CI 1.7, 3.4), suggesting that treating three pts with ENZA instead of BIC would result in one additional pt free of progression or death at the end of 1 year. The NNT to achieve one additional pt with PFS at 2 years was also 2.2 (95% CI 1.5, 3.7). For rPFS, the NNTs comparing ENZA with BIC were 4.7 (95% CI 2.8, 14.6) and 3.0 (95% CI 2.0, 6.1) at 1 and 2 years, respectively. For progression-free PSA, the NNTs were 2.0 (95% CI 1.5, 2.8) and 2.0 (95% CI 1.4, 3.3) at 1 and 2 years, respectively. Conclusions: This analysis supports the superior clinical benefit of ENZA versus BIC in men with m0CRPC. Pts treated with ENZA showed low NNT values across all clinical outcomes and time points. Clinical trial information: NCT01664923.

scholarly journals PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

2016 ◽  
Vol 113 (26) ◽  
pp. 7124-7129 ◽  
Author(s):  
Kanak Raina ◽  
Jing Lu ◽  
Yimin Qian ◽  
Martha Altieri ◽  
Deborah Gordon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Xenograft Model ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Secondary Resistance ◽  
Cellular Models ◽  
Castration Resistant ◽  
Mouse Xenograft Model ◽  
Bet Inhibitors

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

scholarly journals TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

2019 ◽  
Author(s):  
Geun Taek Lee ◽  
Won Tae Kim ◽  
Young Suk Kwon ◽  
Ganesh Palapattu ◽  
Rohit Mehra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Xenograft Model ◽  
Neuroendocrine Differentiation ◽  
Treatment Resistance ◽  
Parental Cell ◽  
Parental Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Expression Levels ◽  
Mouse Xenograft Model

AbstractIn treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.

scholarly journals MicroRNAs as potential therapeutics to enhance chemosensitivity in advanced prostate cancer

2018 ◽  
Author(s):  
Hui-Ming Lin ◽  
Iva Nikolic ◽  
Jessica Yang ◽  
Lesley Castillo ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Potential ◽  
Castration Resistant Prostate Cancer ◽  
Compensatory Mechanisms ◽  
Castration Resistant ◽  
Genome Wide ◽  
Taxane Resistance ◽  
A Genome ◽  
Pc3 Cells ◽  
Taxane Chemotherapy

AbstractDocetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.

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