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Montefiore Gala 2018

Research Round-ups

New Strategy Against Deadly Lung Cancer

New Strategy Against Deadly Lung Cancer—Better treatments are needed for small cell lung cancer (SCLC), an aggressive disease with poor prognosis (5-year survival rate less than 2%). Virtually all SCLCs have inactivating mutations in the same two genes, RB1 and TP53, but all efforts to design drugs to reactivate those genes have failed.  Liang Zhu, M.D., Ph.D., and Edward Schwartz, Ph.D., received a five-year, $2.2 million grant from the National Cancer Institute to try a new approach. Their preliminary studies have shown that SCLC cannot develop in mice when one of RB1’s downstream target proteins (Skp2) is inactivated. The researchers have also identified an inhibitor of that protein that kills human and mouse SCLC tumors. Their new studies could lead to clinical trials of a therapy that might benefit most SCLC patients. Dr. Zhu is professor of developmental & molecular biology, of ophthalmology & visual sciences and of medicine at Einstein. Dr. Schwartz is a professor of medicine and of molecular pharmacology at Einstein. (1R01CA230032-01A1)

Mutated Splicing Factors in Blood Disease

Mutated Splicing Factors in Blood Disease—RNA splicing links segments of messenger RNA into a “complete” template for protein synthesis and is regulated by proteins called splicing factors. Splicing-factor mutations can cause the blood diseases myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how those mutations caused disease wasn’t known. In a study published online on April 22 in Nature Cell Biology, co-first author Gaurav Choudhary, Ph.D., co-corresponding author, Amit K. Verma, M.B.B.S., and their team showed that a splicing-factor mutation triggers formation of  the protein IRAK4-L (an active form of the protein IRAK4), which leads to MDS/AML. The researchers also found that IRAK4-L’s expression in MDS/AML is mediated by the mutated U2AF1 splicing factor. IRAK4-L inhibitors suppressed leukemic growth of AML cells—a strategy that worked even better when the cells had U2AF1 mutations, indicating that U2AF1 mutations make IRAK4-L more targetable.  IRAK4 inhibitors will soon be tested in MDS clinical trials. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. The research was co-led by Daniel Starczynowski, Ph.D., of Cincinnati Children’s Hospital and Jacqueline Boultwood, Ph.D., of the University of Oxford.