Peng Huang, M.D., Ph.D. University of Texas MD Anderson Cancer Center

NEW DRUGS

A Novel Therapeutic Strategy to Overcome CLL Drug Resistance Induced by Stromal Factors

Grant Awarded in 2008

Abstract:

Development of drug resistance in CLL is a major challenge in clinical treatment of CLL patients. There are multiple mechanisms by which the leukemia cells may acquire the ability to survive drug treatment, and stromal (the supporting framework of cells and tissue) influence on CLL cells has recently been recognized as an important factor. The observations that CLL cells have long surviving time in vivo (inside the body) but are prone to undergo cell death when the leukemia cells are isolated from the patient blood and cultured in vitro (outside the body) suggest that the tissue microenvironment may play an important role in the survival of CLL cells.

Recent studies also suggest that the tissue microenvironment may also significantly affect cellular sensitivity to anticancer agents and lead to drug resistance. However, the biochemical and molecular mechanisms underlying the CLL-stromal interactions that present drug resistance remain unclear, and therapeutic strategies to overcome this type of drug resistance remain to be developed.

Our recent study suggests that certain soluble factors from bone marrow stromal cells seem to stimulate CLL cells to produce molecules that are important for the cells to survive under stress and to maintain a stable metabolic state. Removal of such a protective mechanism renders the CLL cells more vulnerable to drug treatment. Based on these observations, we now propose to use biochemical and molecular methods and the CLL-stromal co-culture system to identify the key molecules responsible for promoting the protective mechanisms in CLL cells leading to increased cell survival and drug resistance.

We also plan to test novel compounds and drug combination strategies to effectively disable the protective mechanism caused by stromal-CLL interaction. Because stromal-CLL interactions play a very important role in protecting CLL cells from the cytotoxic action of anticancer drugs, a successful identification of novel agents and drug combination protocols to overcome this type of drug resistance would have significant therapeutic implications.

We anticipate that the results of this research project will further our understanding of drug resistance mechanisms in CLL, and provide important information for the design of new therapeutic protocols to improve the outcomes of clinical treatment of CLL.