Supplement: CCSG Supplement: University of Kentucky Markey Cancer Center - Cancer Support Grant

Systemic chemotherapy is the mainstay of treatment for lung cancer. However, some lung tumors are intrinsically resistant to chemotherapy, and in almost all cases even the initial responders rapidly acquire resistance. Combining novel agents targeting specific resistance pathways with standard of care therapy is one strategy to overcome chemotherapy resistance in lung cancer. We propose a novel approach that will utilize the anti-malarial drug chloroquine (CQ) to induce the secretion of Prostate Apoptosis Response-4 (Par-4, also known as PAWR) protein from normal cells and trigger apoptosis via cell surface GRP78 in lung cancer cells. Our preclinical studies and a Phase 1 clinical trial indicated that CQ or its derivative hydroxychloroquine (HCQ) induces Par-4 secretion from normal cells, resulting in systemically elevated extracellular Par-4 levels and apoptosis in lung tumors. Secreted Par-4 protein induces apoptosis by binding to its receptor GRP78 at the surface of tumor cells and activating the FADD/caspase-8/caspase-3 apoptotic pathway. CQ induces Par-4 secretion from normal cells and not from cancer cells. As GRP78 is selectively expressed on the surface of cancer cells and not normal cells, cancer cells have developed a mechanism to inhibit Par-4 secretion, which can induce autocrine apoptosis. However, limiting amounts of GRP78 on the cancer cell surface can confer resistance to the action of secreted Par-4 protein. By screening an FDA-approved drug library, we identified Crizotinib (CZT), an inhibitor of ALK/MET/ROS1 receptor tyrosine kinases that is used to treat ALK+ lung tumors. CZT is an NCI-IND agent. We noted that CZT induces GRP78 on the surface of cancer cells and complements the action of Par-4 secreted by normal cells. Based on our Preliminary Studies, we hypothesize that CQ+CZT combination will bypass therapy resistance mechanisms and induce growth inhibition of lung tumors, regardless of their Kras, p53, and ALK/MET/ROS1 status. We will determine the growth inhibitory effect of Par-4, induced by CQ from normal cells, in conjunction with CZT in lung patient-derived xenografts (PDXs) from PDXNet and the PDMR database. PDXs available from these sources will be selected to recapitulate the key molecular traits of lung cancer. All treatments in the mice bearing PDXs will be performed by Dr. Ramaswamy Govindan, Principal Investigator of Washington University PDX Development and Trial Center (WUPDTC) at the Siteman Cancer Center, and the mouse and PDX tissues will be analyzed for molecular indicators of CQ+CZT action by Drs. B. Mark Evers and Vivek M. Rangnekar, at the Markey Cancer Center. Our studies will elucidate the mechanisms of CQ+CZT anti-tumor effects, and harness them in future clinical trials to overcome therapy resistance in lung cancer. This Administrative Supplement is well within the scope of the Markey Cancer Center – P30 Cancer Center Support Grant, which includes studies on the role of Par-4 in lung cancer in its Cancer Cell Biology and Signaling Program, and Developmental Therapeutics Program.