Developing Novel Therapeutics for Endocrine Cancers
The Mitsiades lab is committed to being a national leader in improving the lives of patients with endocrine cancers and other malignancies, via a rapid pace of groundbreaking biomedical scientific discovery and its translation to patient care.
Steroid hormones can play a key regulatory role in several malignancies, including breast, prostate and endometrial cancers, promoting cell proliferation and survival. As a result, the estrogen receptor (ER), androgen receptor (AR) and progesterone receptor (PR) are validated therapeutic targets for breast, prostate and endometrial cancer treatment, respectively. However, resistance to the available endocrine therapies develops frequently in these cancers, thus necessitating the development of better therapies.
Androgen deprivation is the standard first-line systemic treatment for advanced prostate cancer, but clinical resistance eventually develops. This clinical state, previously mislabeled as “hormone-refractory” or “androgen-independent”, is more appropriately described as “castration-resistant”, as the AR signaling axis remains active in a substantial subset of these tumors, despite castrate levels of peripheral testosterone, due to a variety of mechanisms (read more about prostate cancer research projects in the Mitsiades Lab). Recent advances, such as abiraterone (androgen synthesis inhibitor), MDV3100 (second generation anti-androgen) and other similar agents, are opening exciting therapeutic opportunities in castration-resistant prostate cancer (CRPC) management and offer hope for even more effective future therapies.
The steroid receptor coactivators (SRC-1, -2 and -3) are key pleiotropic coactivators of ER, AR, PR, other transcription factors and other proteins necessary for cancer cell proliferation and survival signaling. The SRCs are necessary for steroid hormone signaling in health and disease and represent an important therapeutic target in endocrine-related neoplasia. The SRCs can integrate input from other signaling cascades, allowing for cross-talk with other growth and survival pathways (e.g. kinases/phosphatases, acetyltransferases/deacetylases, etc) that can regulate SRC protein stability and activity, allowing for enormous plasticity of the steroid hormone signal, but also for numerous mechanisms of signal amplification in a ligand-independent manner. This signal amplification can be exploited by prostate and breast cancer cells to survive in a low androgen and low estrogen environment, respectively. For example, the E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) plays a critical tumor suppressor role in prostate cancer cells, promoting the turnover of SRC-3 protein and suppressing AR transcriptional activity. This tumor suppressor effect is abrogated by the prostate cancer-associated SPOP mutations (read more about role of SPOP in prostate cancer). Our hypothesis is that inhibitors of the expression and/or function of steroid receptor coactivators could overcome endocrine resistance caused by multiple upstream mechanisms, and, thus, have wide therapeutic implications in prostate and breast cancer.