Cell Survival Pathways and Inhibitors in Leukemia

Dartmouth College, Hanover NH

Investigators

Abstract

DESCRIPTION (provided by applicant): Tumors characteristically exhibit mutations that enhance cell proliferation and survival. Two well-recognized cell survival pathways are RAF to MEK to ERK and PI3-kinase to Akt. Many inhibitors of these pathways are now in clinical trials or at earlier stages of development. However, early results suggest these inhibitors are more likely to suppress growth than kill the tumor cells. Our recent observations have demonstrated that such inhibitors may be more valuable when used in combination with more traditional anticancer agents. Specifically, it has been shown that a MEK inhibitor can dramatically enhance the rate of apoptosis induced by vinblastine in myeloid leukemia ML-1 cells and HL6O cells. However, U937 cells are insensitive to the MEK inhibitor but are sensitized to vinblastine by an inhibitor of PI3-kinase. These observations have led to the hypothesis that different leukemias preferentially use different survival signaling pathways, and that by defining which pathway a specific leukemia uses, effective drug combinations can be individualized for that patient. The goal of this project is to study freshly-isolated human leukemia cells and define the frequency with which they are sensitized to chemotherapy by inhibitors of these two cell survival pathways. The specific aims are to assay leukemia cells for phosphorylation of ERK and Akt as indicators of the signaling pathways used, and to combine inhibitors of these signaling pathways with vinca alkaloids ex vivo to determine the rate of induction of apoptosis. Additional experiments will determine whether normal leukocyte progenitors, which do not have an oncogene-enhanced cell survival pathway, are resistant to these drug combinations thereby suggesting such a therapy may be selective for the tumor. Finally, activation of Jun N-terminal kinase (JNK) will be assayed in leukemia patients receiving vincristine therapy, to confirm that this pathway is activated at drug concentrations tolerated by patients. Activation of the JNK pathway is necessary for the enhanced apoptosis induced by inhibitors of the Erk and Akt pathways. Successful completion of these aims will identify which leukemia patients might benefit from administration of inhibitors of these signaling pathways, and facilitate the design of clinical trials to test their efficacy in combination with other anticancer agents.