Featured Research Project
A highly interactive group of Developmental Cancer Therapeutics Program investigators focuses on the role of the PIM family of kinases in carcinogenesis and cancer therapy. These highly-regulated serine-threonine kinases are expressed in normal cells in response to many stresses as well as in cancer, and they mediate pro-survival responses. Dr. Andrew S. Kraft and Dr. Michael B. Lilly have collaborated on PIM1 studies for many years, and each has independently identified small molecule inhibitors of the kinase.
Recently, Dr. Bo Cen and Dr. Charles D. Smith have worked with Dr. Kraft on preclinical inhibitor studies, leading to collaborative interactions with other Developmental Cancer Therapeutics Program members,
Dr. Lilly and Dr. Campbell McInnes, and with investigators at other NCI Cancer Centers (UCLA, UC Irvine, University of Colorado, Harvard). Dr. Kraft’s lead compound, SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione pan-PIM inhibitor, kills a wide range of myeloid and lymphoid cell lines. Precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) is especially sensitive, both in culture and xenograft models.
More basic studies by Dr. Kraft’s group include the role of PIM1 in glucose metabolism, TOR signals, and stromal cell functions. Dr. Lilly has described novel PIM1-regulated networks that participate in therapy-induced resistance to chemotherapy, providing a rationale for specific combinations of inhibitors to enhance chemotherapy responses in prostate cancer.
Dr. Kraft and Dr. Yubin Kang (Cancer Immunology) have made the important observation that mice with knock-out of Pim genes have a reduced number of bone marrow stem cells. These PIM-related studies arise from the highly collaborative environment fostered by the HCC. Drs. Kraft, Lilly, and Kang have a weekly joint laboratory meeting, and their groups freely exchange ideas, reagents, cells, and databases from genomic and proteomic studies. Together, their observations suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of cancer.