Today we introduce you to Varsha Gandhi of the University of Texas M.D. Anderson Cancer Center. Ghandi's work has been sponsored by LLS since 2011. Her focus has been on acute myeloid leukemia (AML) and below she describes her current project that is showing great promise.
|"Acute myeloid leukemia (AML) is an incurable disease with a 5-year survival rate of less than 20% and the prognosis has not improved significantly in the last 20 years. Doctors estimate about 12,810 new cases of AML and 9000 deaths in the United States alone in 2009. Given these statistics, there is a clear need for new agents for the treatment of AML. Unfortunately, unlike chronic myeloid leukemia (CML), AML does not have a genetic target. However, a new class of proteins, Pim kinases, has been identified to be overexpressed in AML. Pim kinases are proteins that are involved with the growth and survival of cancer cells and these kinases also mediate acquired drug-resistance. Pim kinases are involved with activation of the expression of genetic information from DNA into RNA, transcription, via co-operation with other proteins. A number of oncogenes, DNA genes that code for proteins that participate in cancer development and progression, have RNA transcripts (“messages”) that are quickly degraded in the cell. By inhibiting the function of Pim kinases, survival of cancers that depend on short-lived RNA is impacted. In addition to its role in transcription, Pim kinases also activate other cellular proteins that are involved with complex signaling pathways in cancer cells. The activation of a number of these Pim kinase targets are needed for leukemogenesis, proliferation, cell survival, and the development of resistance to chemotherapy. Developing new drugs against Pim kinases represent a novel strategy to selectively target leukemia cells. This is feasible because leukemia cells such as AML blasts have significantly higher level of these proteins compared to healthy cells, thus reducing toxicity to normal cells. SGI-1776 is a small molecule that potently and selectively inhibits all three Pim kinases. This is an oral drug and is being developed by SuperGen. This agent is currently in phase I clinical trial for patients with prostate cancer. Desired plasma levels (~1 micromolar) are achieved during therapy without reaching maximum tolerated dose. A new phase I trial with SGI-1776 will initiate in hematological malignancies. Preliminary data in AML leukemia cell lines suggest that SGI-1776 prevents the activation of downstream proteins by effectively blocking the signaling pathways and preventing further cancer cell accumulation. In AML animal models, the drug shows efficacy. Using established AML cell lines and cells from patients with AML, we will investigate Pim kinase inhibitor, SGI-1776, as a new treatment for AML. Knowledge gained from these studies will be used to design new protocols and will provide biomarkers that will be tested during therapy."|