Ovarian clear cell carcinoma (OCCC) carries the worst prognosis across all ovarian cancer subtypes. Currently there is no effective cure for OCCC, novel molecular-targeted therapies and potent new agents without cross-resistance to platinum compounds should be developed in OCCC. ARID1A encodes a core subunit of the SWI/SNF chromatin-remodeling complex and suppresses tumor progression in various types of cancers. Loss-of-function mutations in ARID1A occur in over 50% of ovarian clear cell carcinomas.
This project aims to develop new therapies that target ARID1A mutation, and develop an ARID1A/EZH2/STAT1 based immunotherapy modulator in ovarian cancer. SWI-SNF (SWItch/Sucrose Non-Fermentable) complexes is a critical gene transcription regulator; comprised of at least 29 members, which have collectively been found to be mutated in 20% of all different types of human cancers; the mutation rate in cancers is second frequent, only slightly less than p53. The high mutation rate sets the stage for us to target these mutated cancers while sparing the normal tissue at the same time. The new mutation based therapy does not present any of the side effects that usually affect a patient’s quality of life. Our lab reported that PRC2 complex represses TH1 (a type of T helper cells) type chemokines expression in ovarian cancer, and effector T cell trafficking. However, how the specific antagonism of these two complexes function in antitumor immunity is unknown. The antagonism between Polycomb and SWI/SNF complexes leads us to think that the SWI/SNF complex is required for TH1-type chemokines expression and antitumor immunity, to reversely phenocopy PRC2 repression of TH1-type chemokines gene expression and antitumor immunity. We hypothesize that ARID1A mutation alters immune responses of ovarian clear cell carcinoma and high grade serous ovarian cancer (HGSC), and compromise the current immune checkpoint blockade based immunotherapy. Mechanistically, antitumor immunity of ARID1A is dependent on (or associated with) the physical interaction of EZH2 and STAT1.
This grant was made possible by a generous donation from Ovarian Cycle Atlanta.
Dr. Jing Li is a research fellow at Dr. Weiping Zou’s lab in University of Michigan at Ann Arbor. He earned his PhD degree from the Genes and Development program at University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. During his graduate school study, he has received Gigli Family Endowed Scholarship and a few of other awards. His graduate school research focus on epigenetics modulation of breast cancer stemness. His current research project integrates the advantages of both epigenetics and cancer immunotherapy. Specifically, he is interested in the genetic/epigenetic antagonism of Polycomb and SWI/SNF complex and immune response in the ovarian cancer microenvironment, and the mobilization of immune system to attack ovarian cancer. ARID1A is mutated as high as 50% of ovarian clear cell carcinoma patients (OCCC), is a great model to study and harness ovarian cancer immunity. He hypothesizes that ARID1A mutation alters immune responses of ovarian clear cell carcinoma and high grade serous ovarian cancer (HGSC), and compromise the current immune checkpoint blockade based immunotherapy. Mechanistically, antitumor immunity of ARID1A is dependent on (or associated with) the physical interaction of EZH2 and STAT1, and the methylation enzymatic activity of EZH2 might be also involved.