In collaboration with Dr. Mei-Yi Wu, our labs generated several invaluable genetically modified mouse models to understand the normal physiological and pathophysiological function of ARID4B. Complemented by molecular, cellular, biochemical, and genomic approaches, our studies are the first to shed light on the critical role of ARID4B in development, breast and prostate cancers, and the first to provide insight into the molecular mechanism of its action.
While our studies continue to reveal the oncogenic function of ARID4B in breast and prostate cancers, another challenging question is whether ARID4B can be a therapeutic target for these cancers. No pharmacological inhibitors of ARID4B currently exist. As a first step toward pharmacological inhibition of ARID4B, in collaboration with Drs. Mei-Yi Wu and Samuel Awuah, we undertook the computer-assisted drug discovery approach to identify potential ARID4B inhibitors by screening millions of compounds. This effort led to the identification of several lead hits that pass additional tests, including their ADMET properties. Preliminary results from cell-based assays and Isothermal titration calorimetry (ITC) showed that at least 2 of these prioritized lead compounds directly bind to an important functional domain of ARID4B at low micromolar values (3.5 and 1 μM). These compounds also inhibited transcriptional activation of ER target genes and exerts strong anti-proliferative effects in a panel of ER+ breast cancer cells with EC50 at low μM values. Our current and future efforts focus on: (1) Continue strategic structural modifications of current leads in hopes of obtaining more potent new compounds; (2) Solving the co-crystal structures of ARID4B and inhibitors in collaboration with a structural biologist from University of Colorado; and (3) Use pre-clinical mouse models to identify compounds with favorable PK and PD. Our ultimate goal is to develop first-in-class small molecule inhibitors of ARID4B for breast cancer treatment. These inhibitors represent new therapeutic approaches targeting the drivers of breast cancer progression and endocrine resistance by mechanisms that are distinct from the actions of current antiestrogens.
Collectively, our work has resulted in several grant applications and publications in highly regarded journals. It is my strong conviction that our research will continue to be productive for years to come and is certain to exert significant impact in the field of cancer biology.
(1) I serve as director of the (Bioc 6224). I am responsible for the re-design of half of the curriculum to introduce new and advanced lab techniques to the students in the MS program. I also teach and supervise students when they applied the new techniques and knowledge in actual experiments to gain hand-on experience.
(2) I am a member of the teaching team for the Molecular Oncology and Epigenetics (CANC8222, 3 instruction hours, directed by Dr. Xiaoyan Zheng).
I continue to provide the following service to the department, SMHS, and the scientific community.
(1) chair the department multi-user equipment committee.
(2) ad hoc reviewer for numerous scientific journals.
(3) NIH Oncology Fellowships Study Section
(4) scientific reviewer for DoD Breast Cancer Research Program.
(5) member of the departmental MS program admission committee.
(6) member of the faculty mentoring committee for Mamta Gupta.
(7) Abstract review for the Endocrine Society Annual Meeting 2022.