High-Throughput Screens for Estrogen Receptor Pharmacodynamic Markers and Small Molecules that Destabilize the Estrogen Receptor
Abstract
The estrogen receptor (ER) sustains the growth of most breast cancers, and drugs that either decrease the body s ability to make estrogen or block estrogen s ability to stimulate the ER are mainstays of breast cancer treatment. Unfortunately, almost all patients with metastatic breast cancer will eventually become resistant to such drugs and succumb to their disease. In some cases, this is because the ER has acquired a mutation that (1) allows it to be active in the absence of estrogen and/or (2) prevents it from being recognized by conventional ER blocking drugs. We need better ways of monitoring ER activity so that we can assess whether current and future drugs designed to inhibit the ER are working. Moreover, it would be highly desirable to have drugs that inhibit ER in different ways because a proven way to decrease the emergence of resistance is to combine drugs that have distinct mechanisms of action. One goal of this proposal is to develop new ways to monitor ER activity, exploiting the fact that the ER activity regulates the abundance of other proteins ("markers") that could then be measured. Another is to identify drugs that cause the ER to be degraded in cells by binding to a protein that indirectly regulates ER stability or by binding directly to a region of the ER that is different from the region recognized by conventional ER-blocking drugs. The overarching challenge that will be addressed is to eliminate the mortality associated with metastatic breast cancer. The patients to be helped are those with ER-positive breast cancer, especially those with metastatic disease. The clinical applications would be (1) tools for monitoring whether the ER is effectively inhibited in patients treated with drugs that block estrogen production or ER activity and (2) new drugs for inhibiting the ER. The tools for monitoring ER activity could be ready for clinical testing within 1-2 years. Initially the application of these tools will likely require a tumor biopsy to measure the marker of interest. It is hoped, however, that some of these markers could eventually be measured in body fluids (e.g., blood) or be imaged using a suitable antibody that has been labeled with a radioactive tag suitable for radiological studies (e.g., PET scanning). Regarding novel ER inhibitory drugs, it is possible that our screens will identify known drugs that could then be tested almost immediately for their ability to inhibit ER in patients. A more likely outcome is that our screens produce chemicals that will need to be modified to improve their "drug-like" properties before testing in man. This work could take 2-5 years and would likely take place at a biotechnology or pharmaceutical company. We would hope, within the timeframe of this proposal, to deliver knowledge of proteins that, when inhibited, lead to loss of ER and chemicals that are good starting points for drug discovery efforts.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510568
Entities
People
- William G. Kaelin
Organizations
- Dana–Farber Cancer Institute
- United States Army