KSEF RDE: Novel Small Molecule Inhibitors Targeting Cancer Growth via EGFR

Therapeutics for treating cancer are among the primary goals of health research. Tumors activate specific pathways that drive cell growth, and therapeutic agents that target these pathways are in development for multiple types of cancer. One of the most attractive targets is the epidermal growth factor receptor (EGFR), which is inhibited by the cancer drugs erlotinib and erbitux. These drugs extend patients' survival, but are most effective in patients expressing rare mutants of EGFR. We have identified a protein that drives tumor progression and binds to the wild-type EGFR, which most tumors produce. Pgrmc1 (progesterone and growth factor receptor mitogenic complex 1) is related to cy1ochrome b5 and binds to heme, suggesting a role in cellular redox reactions. Pgrmc1 is over-expressed in tumors, and we have found that Pgrmc1 promotes proliferation, invasion and tumor progression. A number of studies have implicated Pgrmc1 in cell signaling, and we have found that Pgrmc1 forms a complex with EGFR that maintains EGFR at the plasma membrane. Furthermore, we have developed a small molecule that binds to Pgrmc1, alters its heme binding properties, disrupts EGFR stability and induces tumor cell death. The aims are as follows. (1) Determine the extent to which Pgrmc1 inhibitors are active in vivo for breast, colon and ovarian cancer cells with differing EGFR status. (2) Determine the molecular features of Pgrmc1 inhibitors that are critical for their biochemical and biological activity. We will compare drug susceptibilities in cancer cells expressing normal and elevated EGFR levels and will perform a variety of in vivo tumor formation assays. The goal of the research is to perform pre-clinical trials of a novel anti-cancer agent and to optimize the structure of the compound. while the long-term goal is to proceed to clinical trials with the optimized inhibitors.