PP2A Activation as a Therapy for AR-Addicted Refractory Castration-Resistant Prostate Cancer

Abstract

The aims of this proposal are to elucidate the mechanism of restoration of AR-signaling in enzalutamide/darolutamide/apalutamide refractory metastatic castration-resistant prostate cancer with specific emphasis on understanding the mechanism of PP2A loss and evaluating its activation by SMAPs (small molecular activator of phosphatase) as a potential novel therapy. We hypothesize that AR-driven transcriptional addiction displayed by anti-androgen resistant cells is caused by hyperphosphorylation of core transcriptional complex consisting of AR, MED1, and BRD4 due to the persistent CDK7 kinase activity and concomitant loss of PP2Aphosphatase activity. We will test this hypothesis by pursuing the following three specific aims, Aim 1: Investigate the PP2A loss associated AR addiction in second generation anti-androgen refractory CRPC. Study the PP2Arestoration on pAR-MED1-BRD4 complex and AR-signaling in anti-androgen refractory CRPC. Aim 3: Evaluate the reactivation of PP2A by SMAPs as a therapeutic strategy in the enzalutamide refractory CRPC.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2022
Accession Number
AD1193697

Entities

People

  • Irfan Asangani

Organizations

  • University of Pennsylvania

Tags

DTIC Thesaurus Topics

  • Addiction
  • Androgen Receptors
  • Androgens
  • Biomedical Research
  • Cancer
  • Castration
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Demographic Cohorts
  • Diseases
  • Gene Expression
  • Mass Spectrometry
  • Medical Personnel
  • Molecules
  • Neoplasms
  • Prostate
  • Prostate Cancer
  • Proteins
  • Small Molecules
  • Standards
  • United States

Fields of Study

  • Biology

Readers

  • Molecular Biology and Genetics
  • Oncology
  • Prostate Cancer Biology.