Project 2: Targeting the Bone Marrow Microenvironment in ALL
Geoffrey Uy, MD, and Daniel Link, MD
Photomicrograph of mouse bone marrow. The hematopoietic stem cell niche is defined by endothelial cells (red) and CXCL12-abundant reticular (CAR) cells (green). Hematopoietic (blood) cells are blue.
The prognosis of adult patients with relapsed acute lymphoblastic leukemia (ALL) is poor. In ALL, resistance to chemotherapy is mediated, in part, by key growth and survival signals that leukemic cells receive from the bone marrow microenvironment. In this project, we will target leukemia-stromal interactions as a strategy to sensitize leukemic cells to chemotherapy. Preclinical studies performed by our group suggest that treatment with granulocyte-stimulating factor (G-CSF) may provide a potent and well-tolerated method to disrupt the leukemia niche in the bone marrow. There is strong evidence that CXCL12, through interaction with its major receptor CXCR4, provides a key survival signal for normal and malignant lymphocytes. We hypothesize that the combination of a G-CSF and a CXCR4 antagonist will cooperate to disrupt leukemia-stromal cell signals, rendering ALL cells more sensitive to chemotherapy.
In Aim 1, we will use preclinical mouse models of ALL to optimize and define the mechanisms by which G-CSF and CXCR4 inhibitors disrupt the leukemic niche to sensitize ALL to chemotherapy. In Aim 2, we will conduct a pilot study combining G-CSF and a CXCR4 inhibitor for patients with relapsed or refractory ALL. Correlative studies will quantify changes in the bone marrow microenvironment and assess ALL cell proliferation and survival. The goal of this study is to translate fundamental observations made by our group on the effects of G-CSF and CXCR4 signaling on lymphocyte development in order to improve the clinical outcome of adults with ALL. This study will provide critical information about the safety and feasibility of this approach, which will be used as the basis for a larger randomized study testing G-CSF and CXCR4 antagonists as chemosensitizing agents in ALL.