Delineating the mechanisms of androgen receptor activation function-1 antagonists for development of novel prostate cancer therapeutics

Information

  • Research Project
  • 9868279
  • ApplicationId
    9868279
  • Core Project Number
    R01CA105304
  • Full Project Number
    5R01CA105304-15
  • Serial Number
    105304
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    4/1/2004 - 20 years ago
  • Project End Date
    1/31/2022 - 2 years ago
  • Program Officer Name
    ALLEY, MICHAEL C
  • Budget Start Date
    2/1/2020 - 4 years ago
  • Budget End Date
    1/31/2021 - 3 years ago
  • Fiscal Year
    2020
  • Support Year
    15
  • Suffix
  • Award Notice Date
    2/6/2020 - 4 years ago

Delineating the mechanisms of androgen receptor activation function-1 antagonists for development of novel prostate cancer therapeutics

Treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (androgen) by surgical and pharmacological castration. Unfortunately, this form of therapy is not curative and eventually the disease will return in a castration resistant form. Once the disease is castration resistant, the survival time is approximately two years before the patient will succumb to his disease. To develop new therapies, a target must be known. Our laboratory identified the N-terminal domain of the androgen receptor as a novel therapeutic target for drug development. This target is supported by data showing that targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified EPI and sintokamide as first in class of antagonists to androgen receptor N-terminal domain. These compounds were both specific and bind to the N-terminal domain of androgen receptor. However, they appear to have different mechanisms of action. Now we draw on this progress and in Aim 1 we propose to characterize the mechanism of sintokamide that causes inhibition of androgen receptor activity. Aim 2 will determine the molecular mechanisms of androgen-repressed genes to yield clues about potential acquired resistance, possible combination therapies, and pharmacodynamic biomarkers. Aim 3 will elucidate binding characteristics. Aim 4 will test combinations of compounds versus monotherapies in vivo using human prostate cancer xenografts. These novel inhibitors to the androgen receptor N-terminal domain are the only ones available for an N- terminal domain of any steroid hormone receptor and represent a new class of androgen receptor antagonists. All data generated will be novel and provide new insight into potential mechanisms of resistance, drug development, and reveal possible pharmacodynamic markers.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    R01
  • Administering IC
    CA
  • Application Type
    5
  • Direct Cost Amount
    261117
  • Indirect Cost Amount
    14732
  • Total Cost
    275849
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    395
  • Ed Inst. Type
  • Funding ICs
    NCI:275849\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    DMP
  • Study Section Name
    Drug Discovery and Molecular Pharmacology Study Section
  • Organization Name
    PROVINCIAL HEALTH SERVICES AUTHORITY
  • Organization Department
  • Organization DUNS
    203769653
  • Organization City
    VANCOUVER
  • Organization State
    BC
  • Organization Country
    CANADA
  • Organization Zip Code
    V5Z 4E6
  • Organization District
    CANADA