PI: Ajay Maker, M.D., Assistant Professor, Surgery, Microbiology and Immunology
Title: Utilizing altered glucose metabolism to selectively sensitize tumor cells to TRAIL
TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family, induces apoptosis by activating the extrinsic pathway through death receptors DR4/5. It has been shown to induce apoptosis preferentially in cancer cell lines with little or no effect on normal tissue. As a result, TRAIL treatment has broad potential in cancer therapy, however, many tumors demonstrate both inherent and acquired resistance to TRAIL treatment.
Due to increased tumor cell glucose uptake and glycolysis, glycolytic inhibition with the glycolysis inhibitor 2-deoxy-D-glucose (2DG) has also been studied as an anti-cancer strategy. Though 2DG has been well-tolerated in clinical trials, its anti-tumor function appears limited to hypoxic conditions due to the ability of tumor cells to compensate inhibited glycolysis with increased aerobic respiration. One of the observed effects of tumor cell 2DG treatment, however, is upregulation of death receptor surface expression. As a result, 2DG may synergize with TRAIL treatment to dramatically increase apoptosis in TRAIL-resistant tumors.
Colorectal cancer is the second most common cancer diagnosis in the United States, and a leading cause of cancer related death. Surgery is the mainstay of treatment for early stage disease, however, over half of all patients will present with advanced or metastatic disease. In these patients, disease recurrence is common, and long-term survival is limited. For these patients, new therapeutic strategies are needed. Many colon cancers are TRAIL resistant and insensitive to 2DG treatment alone, though it is interesting that 2DG is preferentially taken up by colon cancer cells, a property utilized in PET scanning for staging of this disease. The long term goal of our research is to utilize inherent cancer cell glucose dysregulation as a means to provoke durable anti-tumor responses. Our central hypothesis is that glycolytic inhibition of colon cancer cells increases sensitivity to oxidative stress and to death receptor induced apoptosis. Our specific aims include:
Specific Aim 1: a.) Determine the in vitro and in vivo effect of tumor cell exposure to 2DG combined with the death receptor ligand TRAIL. b.) Determine the effect of 2DG treatment on death receptor expression. Our working hypothesis is that 2DG is readily absorbed by colon cancer cells and increases expression of mediators of the extrinsic apoptosis pathway.
Specific Aim 2: Determine the effect of tumor cell exposure to 2DG combined with promoters of oxidative stress. Our working hypothesis is that 2DG pre-treatment affects the anti-tumor activity of oxaliplatin, a standard-of-care chemotherapeutic agent in colon cancer that inhibits thioredoxin reductase, a protector of oxidative cell stress.
Using the principle that tumor cells metabolize glucose more than normal cells, this project aims to selectively identify and sensitize only cancer cells to the effects of a potent anti-tumor therapy utilizing a novel combination of agents that have already safely been used in humans.