Research: Laboratory Program
David E. Modrak, Ph.D.

Dr. Modrak is a Junior Member at GSCC. He received his Ph.D. from Indiana University, Bloomington, working with Dr. John Richardson on the RNA transcription termination factor rho. In his post doctoral training with Dr. Stuart Levy at Tufts University School of Medicine, Boston, he investigated the contribution of multiple mechanisms to the multidrug resistance phenotype in cancer. He has been with GSCC from 1997.

Dr. Modrak's current research interests are centered around novel methods to target tumors with therapeutics in a tumor-specific manner and, in particular, to do so in a way that circumvents drug resistance. Drug resistance is a major factor in the failure of cancer treatment. All too frequently, cancer which reestablishes itself after chemotherapy will do so in a drug resistant form. Worse still, is the likelihood that the cancer will be multidrug resistant, i.e.: resistant to the chemotherapeutic used during treatment and to several other unrelated drugs. Dr. Modrak's lab is approaching this problem from two sides: increasing the sensitivity of the tumor to chemotherapeutics, in order to reduce the chance that any cancer cells will survive, and inhibiting specific proteins involved in drug resistance.

Evidence suggests that ceramide, generated from a distinct subcellular pool of sphingomyelin (SM) by the action of sphingomyelinases, may be used by cells to propagate apoptotic signals in response to a variety of cytotoxic agents. Since most tumor cells have altered lipid metabolism, it is possible that the intracellular pool of SM used for signaling is decreased. To overcome this, we have attempted to increase the SM content of all intracellular compartments with exogenous SM and examined the impact on cellular chemosensitivity to 5-fluorouracil (5FU) and irinotecan. The data suggest that the efficacy of these two chemo-therapeutics for the treatment of human colonic tumor xenografts can be enhanced by the use of exogenous SM. Furthermore, this enhancement may be due to a reversal of the attenuation of the apoptotic signal found in cancer cells without inducing significant hematopoietic, hepatic or renal toxicity.

P-glycoprotein (Pgp) expression is a contributing factor to drug resistance in many kinds of cancer. Inhibition of Pgp activity would theoretically increase the tumors' drug sensitivity and lead to greater efficacy of chemotherapy. Unfortunately, the use of small molecule inhibitors of Pgp for this purpose results in increased drug sensitivity of certain normal tissues which constitutively express Pgp, most notably liver, kidney and blood cells, and reduces the maximum dose a patient can tolerate. Therefore, unless tumor-associated Pgp activity can be inhibited specifically, the full potential of targeting Pgp function may not be realized. With this in mind, we have created a bispecific antibody (bsAb) possessing one arm which binds to a tumor associated antigen, carcinoembryonic antigen (CEA), and one arm which binds to, and inhibits, Pgp. Initial characterization of this bispecific antibody shows that, in vitro, it binds to both CEA and Pgp and inhibits Pgp function. This bsAb is more potent than other known non-tumor specific drugs, such as verapamil. As both of the parental antibodies, from which this bsAb was derived, are known to bind to their targets in vivo (e.g.: CEA and Pgp), this antibody has great potential to reverse drug resistance in a tumor-specific manner.

1. Modrak DE, Gold DV and Goldenberg DM. Sphingolipid targets in cancer therapy. Molec. Cancer Therapeutics 5: 200-208 (2006).
2. Modrak DE, Jones G and Draper MP. "Genomic instability and the microenvironment in the evolution of drug resistance in cancer." (2005) "Frontiers in Antibiotic Resistance," eds.: White, D.G., Alekshun, M.N. and McDermott, P.F. Chpt. 37, pg 500-13. American Society for Microbiology Press, Washington, D.C.
3. Draper MP, Jones G, Gould CJ and Modrak DE. "Overview of the mechanisms of resistance to anticancer agents." (2005) "Frontiers in Antibiotic Resistance," eds.: White, D.G., Alekshun, M.N. and McDermott, P.F. Chpt. 36, pg 473-99. American Society for Microbiology Press, Washington, D.C.
4. Modrak DE. Measurement of ceramide and sphingolipid metabolism in tumors: Potential modulation of chemotherapy in Methods in Molecular Medicine, Blumenthal, R.D., ed., (2005) vol 2, pgs 183-96, Humana Press, Totowa, NJ.
5. Modrak DE, Cardillo, T.M, Newsome G, Goldenberg DM and Gold DV. Synergistic interaction between sphingomyelin and gemcitabine potentiates ceramide-mediated apoptosis in pancreatic cancer. Cancer Research 64: 8405-10 (2004).
6. Modrak DE, Rodriguez MD. Blumenthal RD, Lew W, Gizas LC and Goldenberg DM. Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts. Int J Oncol 20: 379-384 (2002).