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Eur Urol. 2019 Jun 19. pii: S0302-2838(19)30449-X. doi: 10.1016/j.eururo.2019.05.042. [Epub ahead of print]

Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts.

Author information

1
Department of Urology, University of Washington School of Medicine, Seattle, WA, USA; Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
2
Department of Urology, University of Washington School of Medicine, Seattle, WA, USA.
3
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
5
Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
6
Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.
7
Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.
8
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
9
Department of Urology, University of Washington School of Medicine, Seattle, WA, USA; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.
10
Department of Urology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: ecorey@uw.edu.

Abstract

BACKGROUND:

Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects. Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT.

OBJECTIVE:

To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response.

DESIGN, SETTING, AND PARTICIPANTS:

A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance.

INTERVENTION:

Testosterone cypionate.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively.

RESULTS AND LIMITATIONS:

A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression.

CONCLUSIONS:

SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT.

PATIENT SUMMARY:

Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

KEYWORDS:

Androgen deprivation therapy; Androgen receptor; Castration-resistant prostate cancer; Enzalutamide; Patient-derived xenografts; Supraphysiological testosterone; Testosterone

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