Development of Nuclear Receptors and Co-Regulators as Diagnostic and Therapeutic Targets in Breast and Lung Cancers

A growing body of data points to nuclear receptors (NRs) and their co-regulators (CoRegs) as key drivers of cancer cell growth. We believe investigating NRs and CoRegs as a group for their role in cancer has the unprecedented potential to:

  1. Provide unique sets of biomarkers for prognosis and diagnosis of lung/breast cancer;
  2. Provide a tractable set of tools to investigate the molecular mechanisms governing the genesis, maintenance and progression of lung/breast cancer cells; and
  3. Identify new NR- and CoReg-based therapeutic targets for treating patients on an individual basis using a “personalized medicine” approach. This strategy differs from those based on large, complex, open-ended genome-wide studies by examining a defined group of transcriptional regulators with well-characterized mechanisms of action that, in many cases, are also known to be key therapeutic targets. Efforts that combine conventional chemotherapy with targeted therapies against NRs and CoRegs also may be particularly effective. While promising, this approach will have to take into account complex patterns of expression of the superfamily of NRs and CoRegs in individual breast and lung cancers to be successful.

The overall goal of this Cancer Prevention and Research Institute of Texas (CPRIT) MIRA Project is to be able to sample a breast or lung cancer patient’s tumor, profile the tumor for quantitative expression of 48 NRs and 80 CoRegs, and from this information determine the prognosis of that tumor, and most importantly to use this information to develop and test new NR-targeted therapies alone or in combination with chemotherapy for each patient. For example, if the NR PPAR-gamma is expressed in a patient’s tumor, would PPAR-gamma agonists or antagonists be of therapeutic benefit? As another example, if an oncogenic SRC coactivator is overexpressed, can we target this coactivator with a drug designed to bind and degrade the molecule?

Our preliminary evidence suggests we can, and thus we believe there is an opportunity to develop new hormonal and small molecule therapy for these cancers in a “personalized” fashion. This project conducts research in three important areas including: basic mechanistic studies (to understand the precise gene networks and signaling programs of NRs/CoRegs); translational studies (using preclinical models to determine the therapeutic effect of NR/CoReg genetic and pharmacologic manipulation alone and with chemotherapy); and preclinical trial developments (i.e., development of CLIA certified tests for determining quantitative NR/CoReg expression profiles in formalin fixed paraffin-embedded tumor samples).

In addition, as part of the translational applications, we plan to identify and begin testing new drugs that can manipulate NR/CoRegs for therapeutic advantage in breast/lung cancer.

This project is done in collaboration with the Mangelsdorf Lab (Department of Pharmacology, UT Southwestern), Dr. Yang Xie’s Biostatistics Group (Department of Clinical Sciences) and collaborators at MD Anderson Cancer Center (Dr. Ignacio Wistuba) and Baylor College of Medicine (BCM, Dr. Bert O’Malley and Dr. Suzanne Fuqua)