Neil Shah, MD, PhD
Neil Shah, MD, PhD
Human hematologic malignancies
Our lab is interested in improving targeted treatments of human hematologic malignancies. To date, we have largely focused on chronic myeloid leukemia (CML), a disease of the hematopoietic pluripotent stem cell, which can be effectively treated with small molecule inhibitors (e.g Gleevec) of the BCR-ABL tyrosine kinase. BCR-ABL is a promiscuous kinase that is active in virtually all cases of CML and phosphorylates numerous downstream proteins involved in proliferation and inhibition of apoptosis. The natural history of the disease involves acquisition of additional genetic mutations that confer self-renewal properties to a subset of BCR-ABL-positive cells, and transform the disease from a myeloproliferative disorder to an aggressive acute leukemia.
Despite the deep clinical remissions that can be achieved on kinase inhibitor therapy, nearly all patients quickly develop relapse if drug therapy is discontinued, implying persistence of the stem cell pool despite BCR-ABL inhibition. We are interested in understanding molecular mechanisms of disease response, resistance and persistence in human CML, and characterizing cooperative genetic events that are capable of conferring self-renewal properties with the hope of developing therapies that can cooperate with the antiproliferative effects of kinase inhibitors.
Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J and Sawyers CL. (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117-125.
Shah NP, Tran C, Lee FY, Norris D, Chen P and Sawyers CL. (2004) Overriding imatinib resistance with a novel ABL inhibitor. Science 305:399-401.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP and Sawyers CL. (2006) Activity of the ABL Kinase Inhibitor Dasatinib in Imatinib-Resistant Philadelphia Chromosome Positive Leukemias. NEJM 354:2531-2541.