Named Grant:

The Joseph Weksler Memorial Grant

About the Investigator:

Dr. Yisraeli’s group studies the role of RNA binding proteins in helping mediate RNA localization, stability, and translation during development, cell migration, and in different kinds of cancer. He received his BA from Princeton University, his PhD degree in Microbiology from the Hebrew University, and carried out postdoctoral research in Developmental Biology at Harvard University. He is currently an Associate Professor of Developmental Biology and Cancer Biology at the Hebrew University of Jerusalem.

About the Research:

In most tumors, genes that regulate cell division are “dysregulated”: genes that stimulate division (“oncogenes”) are activated when they should not be. This results in uncontrolled proliferation of the tumor cells. Dysregulation usually occurs as the result of mutations in key oncogenes and tumor suppressor genes. In lung cancer, the KRAS oncogene frequently carries mutations that cause it to promote continued rounds of cell division. In addition, activity of KRAS is further enhanced by a second mechanism. The mRNA that encodes KRAS interacts with an RNA binding protein, Igf2bp1, resulting in increased levels of KRAS and enhanced KRAS activity.

The goal of Dr. Yisraeli’s proposal is to develop a new therapy for treatment of lung cancer by inhibiting KRAS and other pro-oncogenic RNAs that are bound by Igf2bp1 in cancer cells. By screening a large library (27,000 compounds), his team identified a lead compound that inhibits binding of KRAS mRNA to Igf2bp1. This destabilizes the mRNA that encodes KRAS, diminishes KRAS protein levels, and inhibits growth of lung adenocarcinoma cells in culture.  Additional RNAs, encoding other oncogenic proteins, are also degraded by administration of the compound. He now proposes to develop enhanced, second generation molecules and test them in pre-clinical mouse models, where they are predicted to inhibit tumor progression and metastasis. This may lead to novel, pharmaceutical-grade precisely targeted compounds that can be used clinically, either as primary or adjuvant therapies for patients suffering from lung carcinoma.