Bhopal Mohapatra, PhD
Dr. Mohapatra is a broadly trained researcher with experience in the fields of molecular and cancer biology, biochemistry, genetics and animal modeling for development and disease. Recurrence, therapy resistance and metastasis remain major challenges in cancer therapy, including breast cancer (BC), accounting for nearly all deaths from cancer. The inability of current therapies to eliminate cancer stem cells (CSCs) is widely believed to underlie these challenges. One of Dr. Mohapatra’s research focuses on elucidating the role of CBL family ubiquitin ligases CBL and CBL-B in the maintenance of cancer stem cell (CSC) in breast cancer. CSCs are ‘drug-tolerant persister’ populations of cancer cells that survive and rapidly adapt to therapy. The identification of CBL/CBL-B dependent tumor initiation and metastasis progression pathways will help to identify druggable targets for metastasis. He has developed a unique genetic model of selective CBL and CBL-B deletion in highly aggressive, triple negative breast cancer (TNBC) model of mammary tumorigenesis C3(1)-TAg.
Furthermore, he is interested in eliminating CSCs in high grade serous ovarian cancer by targeting the cell surface di-ganglioside (GD2), which is highly overexpressed in neuroblastoma, pediatric malignancies and many other cancers including ovarian cancer and an established marker of CSCs and EMT programing using a combination of two clinically-safe drugs, an HDACi (to upregulate GD2 surface expression) and Dinutuximab (antibody against GD2).
- PhD, Biochemistry and Molecular Biology, UNMC
- BVSc & AH (DVM), College of Veterinary Science and Animal Husbandry, OUAT, Odisha, India
The CBL-family ubiquitin ligases (E3s) (CBL, CBL-B and CBL-C) attenuate tyrosine kinase signaling by targeting the kinases and their downstream signaling components to ubiquitin-dependent degradation. Their established role in immune tolerance in cancer has led to recent development of chemical inhibitors against CBL-B, the tumor-intrinsic roles of CBL proteins are little understood, with the bias being that tumor cell inhibition of these negative regulators may accentuate oncogenesis. We established that CBL and CBL-B are redundantly required for the maintenance of hematopoietic, mammary, and intestinal stem cell compartments, and their roles reflect their core function as negative regulators of AKT-mTOR signaling axis. We have new lines of evidence demonstrating the role of CBL/CBL-B in maintenance of CSC function. We hypothesize that tumor-intrinsic CBL and CBL-B expression is required to maintain CSCs in breast cancer. Our long-term goal is to use our unique genetic models and chemical inhibition to establish the tumor-intrinsic role of CBL-family E3s as a rationale to target their function to eliminate CSCs in tumors.
Based on Dr. Mohapatra’s expertise on cancer stem cells and triple negative breast cancer research, he has extended his study to target cancer stem cells in Ovarian cancer. Given the similarity between TNBC and Ovarian cancer, the status of GD2 and rate limiting enzyme GD3S in ovarian cancer was observed to be increased with progression of the disease. Interestingly, we found that treatment of GD2+ ovarian cancer cell lines with vorinostat or panobinostat, FDA-approved HDACi, markedly increased GD2 expression. We hypothesize that ovarian cancer progression is associated with GD2 overexpression and its upregulation by HDACi can be exploited in ovarian cancer using a combination of two clinically-safe drugs, an HDACi and Dinutuximab.
- #Bhat AM, #, *Mohapatra BC, Luan H, Mushtaq I, Chakraborty S, Kumar S, Wu W, Nolan B, Dutta S, Stock MD, Schott M, Meza JL, Lele SM, Lin MF, Cook LM, Corey E, Morrissey C, Coulter DW, Rowley J, Natarajan A, Datta K, *Band V, *Band H (#Co-First Authors; *Co-Corresponding authors). GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior. Sci Rep. 2024 Jun 12;14(1):13523
- #Zutshi N, #Mohapatra BC, Mondal P, An W, Goetz BT, Wang S, Li S, Storck MD, Mercer DF, Black AR, Thayer SP, Black JD, Lin C, *Band V, *Band H (#Co-First Authors; *Co-Corresponding authors). Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance. iScience 2024 June 21; 27(6):109912.