YEARS

2013-2018

AUTHORS

Steven P Balk

TITLE

Androgen Receptor Action in Castration Resistant Prostate Cancer

ABSTRACT

DESCRIPTION (provided by applicant): The past several years have seen a paradigm shift in prostate cancer (PCa) therapy; and it is now becoming widely accepted that androgen receptor (AR) remains active and is a therapeutic target in prostate cancers that relapse after surgical or medical castration (castration resistant prostate cancer, CRPC).'This Program Project brings together a group of investigators with extensive and complimentary expertise in androgens and AR in PCa, and with a track record of accomplishments and productive collaborations. Each project focuses on distinct mechanisms that contribute to AR activity and function in CRPC. Project 1, Steroid Metabolism in Castration-Resistant Prostate Cancer (PI Peter Nelson), focuses on targeting intratumoral androgen synthesis and mechanisms of resistance to abiraterone and other inhibitors of androgen synthesis. Project 2, Basis for Androgen Receptor Antagonist Resistance in CRPC (PI Steven Balk), focuses on mechanisms of action and resistance to AR antagonists. Project 3, Development of Castration Resistance by Alternative AR Splicing (PJ Stephen Plymate) focuses on the role of alternative AR splicing in CRPC. Project 4, Epigenetic Reprogramming of AR Function In CRPC (PI Myles Brown) focuses on the AR transcriptional program and how it is altered with PCa progression. Core A, Administrative/Clinical/Biostatistics Core (PI Steven Balk, Co-PI Peter Nelson) will coordinate the overall program, provide biostatistical support, facilitate access to patient materials, and consult on approaches to enhance/accelerate translation to the clinic. Core B, Biospecimen and Animal Models Core (PI Robert Vessella), will provide a unique series of PCa xenograft models in conjunction with the expertise and infrastructure to carry out trials of single and combination therapies in these models. Dr. Vessella also directs a very robust biospecimen collection and processing Core, and will provide further access to appropriate clinical materials. Core C, Steroid Analytical Core (PI Trevor Penning), will develop and deploy needed state-of-the-art methods to measure multiple steroid and metabolites in human and mouse samples.

FUNDED PUBLICATIONS

  • Role of diet in prostate cancer: the epigenetic link.
  • HDAC inhibition impedes epithelial–mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer
  • Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor.
  • Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study.
  • Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis
  • Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer.
  • Androgen receptor splice variants determine taxane sensitivity in prostate cancer.
  • MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand.
  • SWOG S0925: A Randomized Phase II Study of Androgen Deprivation Combined With Cixutumumab Versus Androgen Deprivation Alone in Patients With New Metastatic Hormone-Sensitive Prostate Cancer.
  • A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.
  • Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis.
  • Control of steroid receptor dynamics and function by genomic actions of the cochaperones p23 and Bag-1L.
  • Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation
  • Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC).
  • Integrative clinical genomics of advanced prostate cancer.
  • Role of diet in prostate cancer: the epigenetic link
  • Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity.
  • PTEN-deficient tumors depend on AKT2 for maintenance and survival.
  • Mechanisms of the androgen receptor splicing in prostate cancer cells
  • Targeted androgen pathway suppression in localized prostate cancer: a pilot study.
  • The Link Between Androgen Receptor Splice Variants and Castration-Resistant Prostate Cancer
  • Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation.
  • Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer
  • The link between androgen receptor splice variants and castration-resistant prostate cancer.
  • Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation.
  • Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif.
  • Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy.
  • Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.
  • AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.
  • Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer.
  • Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors.
  • HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer.
  • Mechanisms of the androgen receptor splicing in prostate cancer cells.
  • PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy.
  • Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.
  • Androgen biosynthesis in castration-resistant prostate cancer.
  • The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.
  • Pentafluorosulfanyl-containing flufenamic acid analogs: Syntheses, properties and biological activities.
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    55 TRIPLES      17 PREDICATES      56 URIs      9 LITERALS

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    52 sg:title Androgen Receptor Action in Castration Resistant Prostate Cancer
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