Fenghuang Zhan, M.D., is executive director of Myeloma Center Basic Research and the Morrison Family Endowed Chair at UAMS. He serves as a professor in the Department of Internal Medicine and is leader of the Genetics, Genomics and Proteomics faculty. His research is funded by competitive grants of over $3 million. He is a recipient of a $1.8 million grant from the Riney Foundation.
“The most important part of my contribution is to translate my research results into clinic usage to help improve myeloma care,” says Zhan.
Tells about your current research
I’m researching drug resistance and immune therapy in multiple myeloma (MM). The extreme variability in survival among patients with MM suggests that specific genetic lesions, possibly reflected in altered gene expression profile patterns in tumor cells, may account for the divergent clinical outcomes. My laboratory is interested in understanding how the genetic alterations in cancer cells contribute to tumor progression, alter treatment response, and create vulnerabilities that may be targeted therapeutically. Our previous work demonstrates that High NEK2 drives myeloma drug resistance and poor prognosis. Monotherapy with PD-1/PD-L1 inhibitors has shown disappointing results in MM, even though targeting immune checkpoints represents a new and very promising approach for the treatment of many solid tumors and certain types of hematologic malignancies. Is there any relationship between NEK2 and the disappointing results of targeting immune checkpoints in MM? To facilitate our research, we are combining genetic and genomic tools that enable us to explore various aspects of cancer biology in a comprehensive way. Current efforts strive to identify new components of NEK2 networks and characterize their impact on immune checkpoints blockade response. In addition, we are defining new biomarkers for targeting immune checkpoint therapy and developing new strategies for high risk (PR/relapsed) MM patients.
Another research focus is on tumor-initiating cells (TICs) in MM. Although a universally accepted TIC phenotype has not yet been identified, the establishment of a TIC phenotype is critical if we want to fully understand the biology of these cells. Many studies indicate that CD24 has been recognized as a legitimate cancer stem cell marker in multiple cancers. Our studies demonstrated that CD24+ MM cells maintain the features of self-renewal and drug resistance in MM, providing a biomarker for myeloma genesis and targeted therapy. Myeloma tumor-initiating cells (MM-TICs), characterized by increased drug resistance and self-renewal capacity, are very likely responsible for our failure to cure myeloma in the majority of patients. Our goal is (1) To determine how the CD24+ primary MM cells (CD38+CD45–) contribute to drug resistance; (2) To define TIC features; and (3) To develop MM TIC-targeted therapies in vitro and in vivo in a pre-clinical mouse model.
Multiple Myeloma is virtually always preceded by a monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM), which are pre-malignant conditions and more prevalent in the elderly population. MGUS patients are not routinely screened since there is currently no treatment that has demonstrated efficacy in reducing the risk of progression of MGUS to MM. Taking advantage of our expertise in MGUS and MM biology and the area of genomics, with relevant mouse models in hand and availability of exceptional human MGUS resources, we are uniquely positioned to discover the key factors that are associated with MGUS progression. Then we are able to develop novel therapies based on a modulation of MGUS risk factors.