Researchers Rebecca Chan, M.D., Ph.D., assistant professor of pediatrics; Reuben Kapur, Ph.D., Frieda and Albrecht Kipp Professor of Pediatrics; and colleagues had determined that SHP2 was hyperactive in cells with a mutation in the KIT receptor in several types of leukemia, including acute myeloid leukemia and mast cell leukemia. Patients with the mutation were considered to have a poor prognosis.
The researchers noted that patients with the mutation who were diagnosed with gastrointestinal stromal tumors responded well to treatment with the drug Gleevec. However, in patients with other diseases such as acute myeloid leukemia who had the same mutation, Gleevec was much less effective. That, the authors noted, had made it vital to identify other drug targets for diseases with the particular mutation.
Chan and Kapur collaborated with Zhong-Yin Zhang, Ph.D., chair of the Department of Biochemistry & Molecular Biology and a biochemist who had identified a small molecule that inhibits that activity of SHP2, to assess the effectiveness of the small molecule inhibitor in shutting down the protein.
In the laboratory tests the compound, IIB-08, was moderately effective in blocking the activity of SHP2 in samples of patient cancer cells and in mouse models of leukemia. Growth of the laboratory cell lines was reduced and the survival time of the animals was prolonged. However, when combined with other small molecule inhibitors, the impact of the drug was much greater.
“The combination significantly enhanced the survival of the animals bearing the mutation,” said Dr. Kapur, director of the program in hematologic malignancies and stem cell biology at the Herman B Wells Center for Pediatric Research. “It’s more than a synergistic effect. It’s pretty profound.”
The results indicate that SHP2, working with other proteins in the body, induces growth of cancerous cells and that the IIB-08 compound is a promising candidate for blocking that SHP2 activity, Dr. Kapur said.
Principal authors for the work were Raghuveer Singh Mali, Ph.D., assistant research professor of pediatrics, Peilin Ma, M.D., Ph.D., research associate in pediatrics, Lifan Zeng, Ph.D., postdoctoral fellow in biochemistry and molecular biology, and Holly Martin, doctoral student in medical and molecular genetics.
Drs. Chan and Kapur are members of the Indiana University Melvin and Bren Simon Cancer Center.
The research was supported in part by grants from National Institutes of Health: R01 HL077177, R01 HL08111 and CA152194 (Z.Y.Z).