About the Lab
Mitsiades lab is a group of experienced, passionate, highly driven scientists. We believe intellectual creativity, rigorous science, and our utmost determination to improve the lives of patients inflicted with cancer will ultimately lead us to uncover clinically relevant therapeutics.
Our 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.
In detail, our mission is to:
- Promote the values and imperatives of Baylor College of Medicine.
- Lead the next wave of biomedical research and its rapid integration into medical practice, toward the goal of improved human health worldwide.
- Advance excellence in oncology and endocrinology.
- Educate the next generation of leaders in medicine and biomedical research.
- Collaborate with other research groups for the advancement of Science and Medicine and the improvement of human health.
Steroid hormones play a key regulatory role in many malignancies, including breast, prostate, and endometrial cancers, where they promote cell proliferation and survival. Steroid hormones Consequently, 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.
By utilizing genomic, cistromic, transcriptomic, and proteomic data to dissect the various functions of steroid receptors and their coregulators. In particular, we are interested in identifying epigenetic signatures that can be applied as biomarkers to predict disease aggressiveness and response to treatment. We are particularly focused on identifying novel gene targets that can be exploited therapeutically for the treatment of prostate cancer.
Developing Novel Therapeutics for Endocrine Cancers
Functional outputs of steroid receptors can be greatly modulated by steroid receptor coactivators. The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 (also known as TIF2, GRIP1, and NCOA2), and SRC-3 (also known as AIB1, ACTR, and NCOA3) are key pleiotropic “master regulators” of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. 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. SRC over-expression and over-activation occur in numerous human cancers due to a variety of genomic, transcriptional, and post-translational mechanisms, and are associated with poor clinical outcomes and resistance to therapy, suggesting that the SRCs are important therapeutic targets. Surprisingly, the field has noted that often time over-expression and over-activation of SRC (for examples, SRC-3 in prostate cancer) occurs without gene amplifications or mRNA over-expression. Yet, much of the mechanisms underlying over-expression and over activation of SRCs is still poorly understood. 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.
We recently reported that in prostate cancer, prostate specific mutations of the SPOP gene abolished its substrate binding capacities. This resulted in stabilization of SPOP substrates in prostate cancer—androgen receptor and SRC-3—and altered AR transcriptional activity in prostate cancer. Our data suggest that wildtype-SPOP plays a critical tumor suppressor role in prostate cells. In a similar fashion, in collaboration with Dr. Bert O’Malley’s lab, we also demonstrated that the E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3 (Cul3)-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. We are currently working on further deciphering these signaling networks (AR/ER/PR-SRC3-SPOP) and identifying compounds that can suppress these transcriptional programs.
Feel free to explore the project links below to learn more about our novel findings and current ongoing projects in our lab.
Our Funding Sources
We are proud to be funded by the following sources to carry out our research work.