Our proposal details a 5-year training program designed to facilitate the development of the applicant into an independent translational investigator of novel therapeutic approaches to overcome chemotherapy resistance in patients with acute leukemia. Interactions with the bone marrow microenvironment have been implicated as a mechanism of chemotherapy resistance in human leukemias, and signals from the microenvironment appear to foster the proliferation of malignant cells and to protect them from chemotherapy. These signaling pathways represent a novel target for the development of curative treatments. The objective of this application is to understand the role of intrinsic and stromally-mediated Hedgehog signaling in long-term self-renewal and chemo- therapy resistance in poor prognosis B-cell acute lymphocytic leukemia (ALL). The central hypothesis is that bone marrow stroma promotes ALL self-renewal and survival through Hedgehog pathway signaling and that Hedgehog inhibition will restore chemotherapy sensitivity and limit self-renewal in poor prognosis ALL. In order to test this hypothesis, we propose the following specific aims: 1) understand the effects of Hedgehog signaling on chemotherapy resistance in ALL and 2) Understand the role of stromally-mediated Hedgehog signaling in ALL. The research strategy includes the use of human B-ALL cell lines, bone marrow stromal cell lines, and specimens from patients with ALL. The effects of bone marrow stroma and Hedgehog pathway modulation on ALL cells will be measured using in vitro assays of cell growth, proliferation and self-renewal. The effects of combination therapy with chemotherapy agents and Hedgehog inhibitors will be assessed in in vivo models of ALL. In addition to these aims, the candidate has designed a career development program to provide essential skills to her development as an independent translational investigator, including formal coursework in cell biology and cell signaling and additional laboratory training in in vivo models of leukemia. This work is expected to characterize the role of Hedgehog signaling and the bone marrow microenvironment in the long-term self- renewal and chemotherapy resistance in ALL. Ultimately, these results are expected to have an important positive impact as they suggest a novel therapeutic strategy using Hedgehog inhibitors to limit self-renewal and overcome chemotherapy resistance in acute lymphocytic leukemia.
The proposed research is relevant to public health, because understanding of the role of the Hedgehog pathway signaling in promoting chemotherapy resistance in leukemia will suggest strategies to overcome these mechanisms, leading to the development of curative treatments. This work is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will reduce the burden of human disease.
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