Zhiquan Wang, PhD

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States with ~21,000 new cases diagnosed each year. Although CLL is considered an indolent cancer with a median survival of ~10 years, it has a heterogeneous clinical course. About 5% of CLL cases have a very aggressive disease at diagnosis with a 5-year survival of 14-19%; whereas 15-20% of the CLLs have a 5-year survival of 68-72%, and the remaining CLL cases have over 90% 5-year survival. MCL is an uncommon but aggressive subtype of B-cell malignancy that comprises 3% to 6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries. Despite the improved clinical outcomes Bruton's tyrosine kinase BTK inhibitors (BTKi, e.g., Ibrutinib, Acalabrutinib, Zanubrutinib), disease progression is an emerging therapeutic challenge in treated patients. Therefore, there is an urgent need to develop more effective therapies to maintain and enhance BTKi treatment among patients whose tumors develop resistance to BTKi. We will focus on CLL as a model to elucidate the mechanism underlying malignant B cell survival and BTKi therapeutic efficacy. These mechanistic studies will also include MCL. Most importantly, we will test if our discovery can be exploited to improve BTKi efficacy and/or overcome drug resistance during BTKi treatment in B-cell malignancies. Together, completing the proposed studies will lay the foundation for subsequent manipulations that will enhance B-cell malignancy therapies.