Craven S2RPGRMC1: Sigma-2 receptor as a therapeutic target in lung cancer

Lung cancer has the highest mortality rate of any malignancy in the US, and new biomarkers and therapeutic targets are urgently needed. Current treatment regimens include chemotherapy and inhibitors of EGFR, a key receptor in lung cancer. The EGFR inhibitor erlotinib is effective against lung cancer but resistance arises rapidly, and new drug targets are needed for erlotinib-resistant lung cancer. The sigma-2 receptor (S2R) is an intracellular drug binding protein, and it was recently shown that S2R is Pgrmc1 (progesterone receptor membrane component 1), a cytochrome-related protein that associates with EGFR. We have shown that S2RPgrmc1 expression is elevated in lung cancer, is essential for lung tumor growth and metastasis and is secreted into the plasma of lung cancer patients. We have developed a small molecule inhibitor for S2RPgrmc1 that inhibits lung cancer growth in vitro and in vivo. The central hypothesis of this application is that S2RPgrmc1 is secreted by tumors, reflects tumor erlotinib resistance and can be targeted by multiple small molecule inhibitors. The aims of the proposal are (1) test the hypothesis that tumor and plasma S2RPgrmc1 levels in patients receiving erlotinib are a function of response to erlotinib therapy. (2) Test the hypothesis that plasma S2RPgrmc1 reflects lung tumor burden pre- and post- therapy. (3) Test the hypothesis that S2RPgrmc1 inhibitors increase the activity of RTK inhibitors in treating erlotinib-resistant lung cancer in vitro and in vivo. Our long term goal is to develop new therapeutic and diagnostic strategies for erlotinib-resistant lung cancer.