Grant: Operating Grant

Recent large scale analyses of mutations in human cancers have revealed that cancer cells exhibit on average approximately 60 to 90 mutations per tumor, with most of these occurring in genes implicated in a limited set of key regulatory celullar pathways. These results indicate that strategies targeting genetic mutations in human cancers are not probably not the way to develop broad acting chemotherapeutic compounds. However, because most of the mutations in human tumors occur in genes that reside in a small number of cellular processes, a better strategy is to develop drugs that inhibit cellular processes that occur downstream of the cancer causing lesions. We know that one such pathway is the regulation of protein synthesis (called translation), a process that is deregulated in many human cancers and which supports the higher growth rate of tumor cells. This therefore provides a therapeutic opportunity in which we can attempt to specifically turn down the rate of protein synthesis in transformed cells and hence interfere with tumor growth. In the current proposal, we propose to experimentally test this hypothesis by generating mouse cancer models in which we can specifically and reversibly interfere with the process of protein synthesis. These new cancer mouse models will allow us not only to assess the consequences of interfering with translation at the cellular level, but also in the tumor as the cancer cells divide in the mouse. Specifically, we will use a lymphoma cancer model were we can easily monitor if we cause tumor regression or growth inhibition. This proposal takes advantage of novel technology developed to shut down any gene desired in the mouse in an inducible and reversible manner. We expect that our experiments will identify a key vulnerability in cancer cells that will inform us as to the direction to proceed in developing novel molecular-targetted chemotherapeutics