Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.

Throughout my career in science, my work has focused in aspects of steroid hormone (progesterone, estrogen, or androgen) receptor activity in breast and prostate cancers. These interests include not only mechanistic studies of receptor activity in treatment naive tumors, but also the role of these receptors in the evolution of resistance to current therapies.

Despite the development of improved therapies, breast cancer remains a leading cause of mortality in women. While a majority of breast cancers are estrogen receptor (ER) positive and respond to endocrine therapies such as tamoxifen or aromatase inhibitors, as many as 50% of patients experience relapse and progression. Recent data has confirmed continued reliance of these cancers on ER signaling, validating this receptor as a therapeutic target even in a relapsed/metastatic setting. The focus of a majority of my work in breast cancer has been the mechanistic evaluation of methods to target ER activity in this setting of resistance, either through the development of improved receptor antagonists or through the identification of targets downstream of, or impinging upon, ER activity that can serve as secondary targets in this setting. 

Similarly, the androgen receptor (AR) remains a therapeutic target in prostate cancer throughout treatment progression to end stage prostate cancer. Although several AR antagonists have been developed and approved for the treatment of prostate cancer, AR overexpression, as well as mutation and/or truncation, are observed clinically and have been shown mechanistically to render the current AR antagonists ineffective in the advanced prostate cancer setting. As with our work in breast cancer, we have identified pathways downstream of AR that are essential to prostate cancer progression, and our current work is intended to devise treatment regimens that will be effective in lieu of, or together with, AR antagonists.

In my role as a research assistant professor, I have conducted several animal studies evaluating next-to-clinic therapeutics in clinically predictive models of advanced breast and prostate cancer that I have developed throughout the past several years of studies. The entry of some of these therapeutics, or of mechanistically related molecules, into clinical trials in these patient populations validates this approach.

The main focus of my research has been to define the roles of nuclear hormone receptors (NHRs) in the pathogenesis of disease, with a focus on hormone-related cancers. 

During earlier stages of my research career, definition of the structural and molecular determinants of NHR receptor biology and pharmacology was the main focus. Information obtained from these studies was used to guide the development of receptor modulators for therapeutic interventions and to gain insights into the pharmacology of estrogen and androgen receptor ligands. More recently, my research has shifted to define receptor-mediated signaling pathways relevant to the pathogenesis of breast and prostate cancers. One example of this is the definition of signaling pathways downstream of the orphan nuclear receptor, estrogen-related receptor alpha (ERRα) in breast cancer. Using gene expression signature defined in breast cancer cells we demonstrated that the activity of ERRα tracks with poor prognosis in all breast cancer subtypes. We confirmed a causal role for ERRα in breast cancer growth in both cellular and xenograft models of breast cancer. More recently, we further defined the role(s) of this receptor in tumor metabolism and validated its utility as a therapeutic target in triple negative breast cancer (TNBC). In addition to the cancer cell intrinsic effects of ERRα, this receptor is also expressed in T cells and in macrophages. We are currently evaluating the impact of modulating ERRα activity in these immune cells and how that influences tumor biology. 

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The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.