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.
|Luu Tran, Huong; Mahmoudjafari, Zahra; Rockey, Michelle et al. (2016) Tolerability and outcome of once weekly liposomal amphotericin B for the prevention of invasive fungal infections in hematopoietic stem cell transplant patients with graft-versus-host disease. J Oncol Pharm Pract 22:228-34|
|Bray, Whitney M; Bivona, Cory; Rockey, Michelle et al. (2015) Outcomes for newly diagnosed patients with acute myeloid leukemia dosed on actual or adjusted body weight. Cancer Chemother Pharmacol 76:691-7|
|Lin, Tara L; Williams, Travis; He, Jianghua et al. (2015) Rates of complete diagnostic testing for patients with acute myeloid leukemia. Cancer Med 4:519-22|
|Powers, Benjamin; Persons, Diane; Rao, Deepthi et al. (2015) High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA. Case Rep Hematol 2015:343854|
|Aljitawi, Omar S; Xiao, Yinghua; Eskew, Jeff D et al. (2014) Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34âº cells in a murine model of umbilical cord blood transplantation. Blood Cells Mol Dis 52:59-67|
|Howard, Christin R; Lin, Tara L; Cunningham, Mark T et al. (2014) IgG kappa monoclonal gammopathy of undetermined significance presenting as acquired type III Von Willebrand syndrome. Blood Coagul Fibrinolysis 25:631-3|
|Wieliczka, M L; Ganguly, S; Abhyankar, S et al. (2014) Rituximab as a treatment for factor VIII inhibitor in a patient with chronic GVHD. Bone Marrow Transplant 49:588|
|Prochaska, L; Vacek, J; Madan, R et al. (2014) Intestinal ischemia after allogeneic stem cell transplantation: a report of four cases. Transplant Proc 46:1536-9|
|Aljitawi, Omar S; Li, Dandan; Xiao, Yinghua et al. (2014) A novel three-dimensional stromal-based model for in vitro chemotherapy sensitivity testing of leukemia cells. Leuk Lymphoma 55:378-91|
|Brownback, Kyle R; Simpson, Steven Q; McGuirk, Joseph P et al. (2014) Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation. Ann Hematol 93:847-54|
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