2020 Mentored Investigator Grant Recipient — Jianhuang Lin, PhD
Epithelial ovarian cancer (EOC) remains the deadliest gynecological cancer in the United States. EOC is comprised of multiple separate diseases. High grade serous ovarian carcinoma (HGSOC) is the most common subtype (>70% of EOC cases) and accounts for the majority of EOC-associated deaths. To this day, there is no effective single therapy that has proven beneficial for all EOC patients. Thus, there is an urgent need to develop personalized therapeutic strategies by specifically targeting distinct subsets of EOC. In this study, we focus on a subset of EOC which expresses an enzyme called Coactivator-associated arginine methyltransferase 1 (CARM1). CARM1 is frequently overexpressed and functions as an oncogene in several types of cancer. Notably, HGSOC has the highest rate of CARM1 gene amplification and overexpression (~20% combined) among all the cancers, and high CARM1 levels are associated with poor survival in EOC patients. More importantly, patients with CARM1 amplification or overexpression are usually BRCA wildtype (WT) patients, treatment for whom remains a problem due to its low sensitivity the only approved targeted therapy for EOC, known as PARP Inhibitor, a type of medication that usually holds promise for treating BRCA-related cancers. Thus, there is a great need to develop therapeutic strategies against CARM1-expressing EOC for the treatment of BRCA WT EOC. With that, the overall goal of this proposal is to develop a novel strategy for EOC based on CARM1 status.
To target CARM1-high EOC, I screened for potential target pathways that are specifically active in CARM1-high EOC. I identified a pathway called the Endoplasmic Reticulum (ER) stress response pathway that is specifically active in CARM1-high HGSOCs. The ER is a network of membranes found throughout the cell and connected to the nucleus, and functions as a manufacturing and packaging system within that cell. ER stress is caused by the accumulation of unfolded or misfolded proteins within the ER lumen. The ER stress response is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the functions of ER stress response in ovarian cancer remain elusive. My data showed that CARM1-high HGSOC exhibits significantly higher level of ER stress response compared with, for example, CARM1 low HGSOC. Using a drug, B-I09, to inhibit the ER stress response pathway selectively suppresses CARM1-high HGSOCs. Interestingly, it does not do so in CARM1-low or CARM1 knockout HGSOCs. These results suggest that ER stress response inhibition is a unique and exploitable therapeutic vulnerability in CARM1-high HGSOCs. My central hypothesis is that CARM1-high HGSOCs can be therapeutically targeted by the inhibition of the ER stress response to provide novel strategies for the treatment of BRCA WT CARM1-high HGSOCs by targeting the ER stress response pathway.
This grant was made possible in part by funds raised by Jane Rubin and The Mathilda Fund in memory of Jane’s great grandmother Mathilda.
Dr. Jianhuang Lin is currently a Postdoctoral Fellow in the laboratory of Dr. Rugang Zhang at The Wistar Institute, Philadelphia. Dr. Lin received in 2011 a Bachelor’s degree in Bioengineering from Fuzhou University, Fuzhou, Fujian, China, and he obtained his Ph.D. degree from the University of Tsukuba, Japan in 2017. At the University of Tsukuba, Dr. Lin received a full scholarship from the Leading Graduate School Doctoral Program supported by the Japanese government to study cancer epigenetics. To pursue his research interests in ovarian cancer epigenetics and onco-immunology, he joined Dr. Rugang Zhang’s lab in 2018. His current research focuses on developing novel personalized therapeutic strategies by targeting distinct subsets of ovarian cancers. In particular, he is working on CARM1-high epithelial ovarian cancer (EOC) for treatment of BRCA proficient ovarian cancer. In addition, he is also interested in onco-immunology of ovarian cancer. The ultimate goal of his research is to contribute to better treatment outcomes by developing personalized therapeutic strategies.