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The Coffey Lecture: steroidogenic enzyme inhibitors and hormone dependent cancer

Angela Brodie1, Vincent Njar, Luciana Furtado Macedo

  • 1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA. abrodie@umaryland.edu

Urologic Oncology
|December 30, 2008
PubMed
Abstract

Insights

Novel aromatase inhibitors are effective for breast cancer treatment. Inhibitors of 17alpha-hydroxylase/lyase show promise for prostate cancer, with strategies to overcome resistance restoring hormone therapy sensitivity.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Steroidogenic enzyme inhibitors are being developed for cancer treatment.
  • Aromatase inhibitors (AIs) are clinically used for breast cancer.
  • 17alpha-hydroxylase/lyase inhibitors are under investigation for prostate cancer.

Purpose of the Study:

  • To evaluate novel steroidogenic enzyme inhibitors for breast and prostate cancer.
  • To investigate mechanisms of resistance to aromatase inhibitors.
  • To explore strategies to overcome treatment resistance.

Main Methods:

  • Development and preclinical evaluation of novel steroidogenic enzyme inhibitors.
  • Clinical trials of aromatase inhibitors in breast cancer patients.
  • Preclinical studies of 17alpha-hydroxylase/lyase inhibitors in prostate cancer models.
  • Optimization of treatment strategies using intratumoral aromatase xenograft models.
  • Analysis of signaling pathways in tumors resistant to aromatase inhibitors.

Main Results:

  • Aromatase inhibitors demonstrate greater benefit than antiestrogens in breast cancer.
  • Inhibitors of 17alpha-hydroxylase/lyase show potential for prostate cancer treatment.
  • Tumors developed resistance to aromatase inhibitors by up-regulating HER-2 and MAP Kinase signaling.
  • Combined treatment with letrozole and trastuzumab (anti-HER-2 antibody) restored sensitivity and inhibited tumor growth.

Conclusions:

  • Aromatase inhibitors represent an effective new class of agents for breast cancer.
  • 17alpha-hydroxylase/lyase inhibitors hold potential for prostate cancer therapy.
  • Strategies to overcome resistance can restore tumor sensitivity to hormone therapy.

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