Use of EF2K inhibitors to inhibit tumor growth and sensitize cancer cells to existing chemotherapy treatment

DESCRIPTION provided by applicant Eukaryotic elongation factor protein kinase eEF K is a ubiquitously expressed protein that belongs to a family of alpha kinases characterized by an andquot atypicalandquot kinase domain Our recent findings demonstrate that inhibition or genetic inactivation of eEF K protects normal tissues from cytotoxic effects of ionizing radiation and chemotherapeutic agents We have previously generated eEF K deficient animals that have no adverse phenotypes but demonstrate increased resistance to both lethal doses of radiation and doxorubicin induced cytotoxicity This radio and chemoresistant phenotype is accompanied by decreased levels of apoptosis in proliferating tissues Moreover siRNA mediated knockdown of eEF K sensitizes cancer cells to nutrient deprivation and to treatment with chemotherapeutic agent doxorubicin and suppresses tumor growth in the mouse model of breast cancer Thus we expect eEF K inhibitors to exert dual effects in protecting normal tissues while enhancing tumor killing during chemotherapy thereby significantly enhancing the therapeutic index of conventional chemotherapy Several attempts have been made to develop chemical inhibitors of eEF K but the resulting compounds suffered from various limitations such as low specificity for eEF K insufficient potency high serum binding or high toxicity precluding their application in the clinic We have developed a novel screening platform enabling rapid and accurate determination of eEF K phosphorylation activity in vitro Using this platform we have generated a series of new eEF K inhibitors that can be produced with high yields and purity and exhibit high specificity improved potency low serum binding and low toxicity Our preliminary data show that this series of eEF K inhibitors effectively mimics the effects of siRNA mediated knockdown of eEF K expression sensitizing cancer cells to nutrient deprivation and doxorubicin Moreover our lead inhibitor compound reduced doxorubicin toxicity in vivo as evidenced by a reduction of a biomarker of tissue damage In this grant we propose to further optimize our eEF K inhibitor series and to carry out a panel of proof of concept experiments testing the efficacy of these inhibitors in sensitizing cancer cells to nutrient deprivation and doxorubicin treatment and suppressing tumor growth in a mouse breast cancer model It is anticipated that upon completion of this project we will identify an inhibitor of eEF K that will potentiate tumor killing by chemotherapy while protecting normal tissues from the associated toxicity thereby representing an unprecedented approach to cancer therapy PUBLIC HEALTH RELEVANCE Environment within solid tumors is characterized by low vasculature and nutrient deprivation and ability of tumor cells to adapt to these conditions is associated with enhanced malignant potential Our ability to fight these tumors is further limited by the toxic side effects of existing chemotherapeutics In vivo inactivation of eukaryotic elongation factor kinase eEF K has a two pronged anti tumor effect it sensitizes tumor cells both to nutrient deprivation and to chemotherapy We have developed highly specific inhibitors of eEF K and the major goal of the proposed research is to test their efficacy in sensitizing cancer cells to nutrient depletion and to chemotherapeutic agent doxorubicin in cell lines and a mouse model of breast cancer