Assistant Professor of Pediatrics
Department of Pediatrics
Department of Medical & Molecular Genetics
Herman B Wells Center for Pediatric Research
Improved Therapy for Childhood Leukemia
Treatments and cures for childhood leukemia have greatly improved over the last 20 years. However, despite these great steps forward, some forms of childhood leukemia, in particular the myeloid leukemias, remain difficult to treat and are too commonly incurable. My laboratory focuses on particularly lethal forms of childhood leukemia: juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). JMML is a lethal leukemia of children less than 5 years of age characterized by massive overproduction of myeloid cells, in particular macrophages. Unfortunately, JMML is resistant to standard chemotherapy and most afflicted children succumb to disease due to organ infiltration with malignant macrophages, ending terminally in bleeding and infection. With the rigorous treatment of allogeneic stem cell transplantation, the probability of event-free survival at five years following transplantation in only approximately 50%. AML is more responsive to intensive chemotherapy; however, allogeneic stem cell transplantation is often required for curative therapy. Furthermore, children with AML bearing mutations within the receptor protein tyrosine kinase, Flt3, bear a significantly worse prognosis for their chances of achieving disease free survival at 5 years following definitive therapy. Even for children with JMML and AML who survive the aggressive procedure or allogeneic stem cell transplantation, many face life-long morbidities secondary to the transplant procedure such as graft v. host disease and infertility. Clearly, improved therapies for these lethal childhood diseases are urgently needed. Over the past several years, my laboratory has focused on the molecular mechanisms that underlie JMML and AML. We have concentrated on a protein, Shp2, that is commonly mutated in children with JMML (approximately 35% of cases) and that participates in mutant Flt3-induced myeloid leukmeogenesis. The overall goals of the mechanistic-based molecular studies performed in my lab are to define novel molecular targets in these diseases for the rational development of improved and less toxic therapies for JMML and AML. Furthermore, my laboratory is working in collaboration with Zhong-Yin Zhang, Ph.D. of the Department of Biochemistry and Molecular Biology to identify novel compounds with the ability to selectively and potently inhibit Shp2 enzymatic function and to test these compounds in a cellular model of in vivo leukemia developed in my lab. Collectively, my research program meets the criteria of translational research as it is cross-disciplinary (links the study of cell biology in the context of in vivo models of disease (Chan lab) with the discipline of phosphatase enzymatic biochemistry (Zhang lab) in the development of Shp2 inhibitors) and as it is directed toward the goal of improving therapies for specific lethal childhood maladies, thus leading to the betterment of everyday life.