Cancer Cell Intrinsic and Extrinsic Actions of Steroid Hormones in Breast Tumors
Abstract
Until recently it was considered that tumor progression while on an endocrine therapy for the treatment of estrogen receptor-alpha (ER alpha)-positive breast cancer signaled the end of the useful life of the estrogen signaling axis as a target in this cancer. However, fueled in large part by our studies, which have defined the primary molecular determinants of ER pharmacology, there has been a resurgence of interest in this receptor as a therapeutic target, work that has yielded a new class of orally bioavailable Selective Estrogen Receptor Downregulators (SERDs), several of which are currently in clinical trials in patients with metastatic breast cancer. Whereas improvements in patient outcome will likely be observed when these SERDs become available for clinical use, it is our opinion, given their established pharmacological/pharmaceutical properties, that further development of agents that directly target ER alpha within cancer cells will yield only incremental improvements. Thus, we have redirected our efforts to develop strategies to improve the efficacy of existing/emerging endocrine therapies. As with most cancers, engagement of the host immune system offers the greatest potential to eradicate breast cancer although there is substantial evidence that this activity is incompatible with the current approaches used to achieve systemic inhibition of ER signaling. Addressing this potential liability of endocrine therapies is timely with the advent of immunotherapies. The new ideas we are proposing are based on the assumption that currently available therapies, while optimized for their ability to inhibit the cancer cell-intrinsic actions of ER alpha, largely ignore the impact of these drugs on other ER alpha expressing cells involved in tumor pathobiology. Thus, we propose to define the impact of ER alpha/estrogen signaling on immune cell function and tumor immunity in new and established animal models of breast cancer and in breast cancer patients. This information will be used to drive the discovery of the next generation of ER alpha modulators that effectively inhibit ER alpha action in cancer cells but that are optimized for positive activities on tumor immunity using a new drug discovery platform we have developed and validated, which leverages our current understanding of the relationships between ER alpha-coregulator interactions and drug pharmacology.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810064
Entities
People
- Donald P McDonnell
Organizations
- Duke University
- United States Army