Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

Sena, Laura A.; Kumar, Rajendra; Sanin, David E.; Thompson, Elizabeth A.; Rosen, David; Dalrymple, Susan L.; Antony, Lizamma; Yang, Yuhan; Gomes-Alexandre, Carolina; Hicks, Jessica L.; Jones, Tracy; Bowers, Kiara A.; Eskra, Jillian N.; Meyers, Jennifer; Gupta, Anuj; Skaist, Alyza; Yegnasubramanian, Srinivasan; Luo, Jun; Brennen, W. Nathaniel; Kachhap, Sushant K.; Antonarakis, Emmanuel S.; Marzo, Angelo M. De; Isaacs, John T.; Markowski, Mark C.; Denmeade, Samuel R.

doi:10.1172/jci162396

Cited by 19 publications

(31 citation statements)

References 36 publications

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“…In addition to the paired pre- and on-BAT biopsies of metastases from patients with CRPC, the authors used PC cell lines and a CRPC PDX to explore possible mechanisms underlying BAT responsiveness. While PC cell line-based experiments showed that high levels of AR and AR activity were required for SPA response, as previously observed ( 3 , 16 ), patient data demonstrated that AR activity, and not AR abundance, predicted BAT response ( 12 ). This finding may be explained by the fact that AR protein levels do not necessarily correlate with AR transcriptional activity due to different CRPC adaptation mechanisms, such as AR activating mutations, changes in AR coregulators, and expression of constitutively active AR variants.…”

Section: High Ar Activity Is Associated With Clinical Response To Batsupporting

confidence: 68%

“…In this issue of the JCI , Sena et al leveraged sequential paired metastatic specimens, termed “pre-BAT” and “on-BAT”, that were collected from an ongoing clinical trial COMBAT-CRPC (NCT03554317). This single arm, phase II clinical trial enrolled patients with metastatic CRPC whose cancer progressed on an ARSI and treated them with BAT for 12 weeks, followed by a combination treatment of BAT and the anti-PD1 agent nivolumab ( 12 ). Specimens for this study were collected prior to the initiation of treatment with nivolumab.…”

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

“…Using PC patient databases ( 13 – 15 ), the authors identified ten canonical AR target genes and applied Mann-Whitney ranking to generate a signature score, which the authors termed ARA MW . When applied to the COMBAT-CRPC pretreatment sample RNA-Seq data, a high pretreatment ARA MW score predicted clinical responses to BAT in the cohort of 15 patients, suggesting that ARA MW can serve as a biomarker for BAT response ( 12 ) ( Figure 1 ). No collinearity was found among the genes, and ARA MW did not correlate with AR levels across patients.…”

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

“…Sena et al also provide valuable patient data for other investigators to interrogate with respect to BAT response ( 12 ). For example, Qiu et al ( 11 ) defined a pretreatment AR cistrome that predicts response to SPA in PC patient-derived xenografts (PDXs), but, interestingly, this signature does not contain canonical AR target genes nor does it overlap with ARA MW .…”

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

“…Similarly, patients who responded to BAT exhibited a larger decrease in MYC compared with nonresponders. Additionally, patients with decreased MYC also correlated with those that had higher AR activity before treatment ( 12 ). Although the mechanism through which SPA decreases MYC in patients is unknown, a recent report using PC cell lines demonstrated that AR decreases MYC transcription independently of AR chromatin binding.…”

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

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Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

Peinetti¹,

Bilušić²,

Burnstein³

2022

Journal of Clinical Investigation

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Androgen deprivation therapy (ADT) is the longstanding treatment for advanced prostate cancer (PC) because androgen receptor (AR) is the key therapeutic vulnerability for this disease. Bipolar androgen therapy (BAT) — the rapid cycling of supraphysiologic androgen (SPA) and low serum testosterone levels — is an alternative concept, but not all patients respond and acquired resistance can occur. In this issue of the JCI , Sena et al. developed a gene signature indicative of high AR activity to predict patient response to BAT, including a decline in both serum prostate-specific antigen (PSA) and tumor volume. Preclinical models showed that AR-mediated suppression of MYC, known to drive PC, was associated with decreased cell growth following SPA treatment. Because BAT eventually leads to resistance, the authors tested cycling between SPA and AR antagonism in a patient-derived xenograft and observed a delay in tumor growth. These findings represent a major step toward the informed use of BAT for advanced PC.

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Section: High Ar Activity Is Associated With Clinical Response To Batsupporting

confidence: 68%

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

Section: High Ar Activity Is Associated With Clinical Response To Batmentioning

confidence: 99%

See 3 more Smart Citations

Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

Peinetti¹,

Bilušić²,

Burnstein³

2022

Journal of Clinical Investigation

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Clinical and molecular determinants of PSA response to bipolar androgen therapy in prostate cancer

et al. 2023

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Background Bipolar androgen therapy (BAT) is a novel therapy known to be effective in a subset of men with metastatic castrate resistant prostate cancer (mCRPC). A better understanding of responders and nonresponders to BAT would be useful to clinicians considering BAT therapy for patients. Herein we analyze clinical and genetic factors in responders/nonresponders to better refine our understanding regarding which patients benefit from this innovative therapy. Methods mCRPC patients were assessed for response or no response to BAT. Patients with PSA declines of greater than 50% from baseline after 2 or more doses of testosterone were considered to be responders. Whereas, nonresponders had no PSA decline after 2 doses of testosterone and subsequently manifest a PSA increase of >50%. Differences between these two groups of patients were analyzed using clinical and laboratory parameters. All patients underwent genomic testing using circulating tumor DNA (ctDNA) and germline testing pre‐BAT. Results Twenty five patients were nonresponders and 16 were responders. Baseline characteristics between nonresponders and responders varied. Responders were more likely to have had a radical prostatectomy as definitive therapy and were more likely to have been treated with an androgen receptor (AR) antagonist (enzalutamide or apalutamide) immediately before BAT (compared to abiraterone). Duration of prior enzalutamide therapy was longer in responders. Nonresponders were more likely to have bone‐only metastases and responders were more likely to have nodal metastases. Assays detected ctDNA AR amplifications more often in responding patients. Responders trended toward having the presence of more TP53 mutations at baseline. Conclusions BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.

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Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

Fu,

Wang,

Jia

et al. 2023

The Prostate

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BackgroundThe discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co‐factor competition and redistribution. Indeed, AR dual functions are exemplified by locus‐wide regulation of the oncogenic 8q24‐MYC region.MethodsRT‐qPCR assay and public RNA‐profiling datasets were used to assess MYC transcription in androgen‐sensitive cell lines. Public ChIP‐seq and RNA‐Seq datasets were computed to evaluate AR‐MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross‐talks. Bio‐informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen‐elicited distal regulation. Finally, co‐factor re‐distribution were globally tracked between AR and MYC binding sites.ResultsIn this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen‐mediated versus MYC‐mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen‐repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR‐binding site and MYC‐binding site.ConclusionTogether, our findings stratified AR‐MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

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Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

Cited by 19 publications

References 36 publications

Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

Clinical and molecular determinants of PSA response to bipolar androgen therapy in prostate cancer

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

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