Targeting Both Aberrant Metabolism and Cell Proliferation in Cancer Therapy

Mantle Cell Lymphoma (MCL) is an aggressive malignancy that accounts for 5–10% of non‐Hodgkin lymphomas. Upon relapse, MCL is considered clinically incurable, hence it has the worst prognosis amongst all B‐cell lymphomas. Therefore, it is imperative to identify novel therapeutic strategies that effectively target deregulated pathways that contribute to MCL pathogenesis. The hallmark of MCL is the constitutive expression of the G 1 ‐phase cell cycle regulatory oncogene cyclin D1 which is not normally expressed in B‐lymphocytes. This results in uncontrolled cell proliferation. This cyclin D1 driven hyper‐proliferative phenotype is associated with reduced survival in MCL patients. Uncontrolled cell growth results in metabolic reprogramming of the cells to support the energy and biosynthetic needs of the rapidly dividing cells. The changes in genes involved in metabolism result in increased glucose and glutamine uptake and metabolism in tumor cells. We hypothesize that targeting both hyper‐proliferation and altered cell metabolism would be a more effective way to induce cancer cell death. Western blot analysis shows that MCL cells overexpress both cyclin D1 and glutaminase, the enzyme that is critical for glutamine metabolism. Treatment targeting cell proliferation alone, or metabolism alone decreased the cell‐viability of MCL cells. However, greater cytotoxic activity was observed with combination treatment. Our preliminary data suggests that concurrent targeting of both metabolism and cell proliferation in MCL cells has a synergistic effect that enhances the induction of cancer cell death. Support or Funding Information Butler University Holcomb research award