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Lung cancer is the number one cause of cancer death in men and women in the US with more people dying of lung cancer than the combined total from colon, breast and prostate cancer (more than 150K deaths/year). Unfortunately, lung cancer is often diagnosed at advanced or metastatic stages when the disease has already become very aggressive. Lifestyle choices, especially smoking, serves to drive mutation of genes, called oncogenes, that drive the cancer cell growth, survival and metastasis. Current therapeutic approaches, including surgery, radiation, combination chemotherapy, and recent advanced therapies of target inhibitors and immunotherapy, result in 30 percent survival. Unfortunately, that leaves 70 percent of lung cancer patients without any therapeutic options. Many of the smoking-induced lung cancer driver oncogenes, specifically KRAS and MYC, are undruggable by current therapeutic approaches. However, siRNA-induced RNA interference (RNAi) responses have great potential to develop truly precision medicines that can revolutionize the treatment of lung cancer and target the entire “undruggable” genome, including cMYC and all mutant forms of KRAS. Unfortunately, RNAi therapeutics cannot be delivered in cancer cells. Thus, RNAi delivery remains the technological problem to solve. Our high risk/high gain proposal directly tackles the RNAi delivery problem by developing Antibody-RNAi Conjugates (ARCs). ARCs use the exquisite cell targeting selectivity of antibodies that we will link to next-generation RNAi triggers, called siRNNs, that our lab recently developed. We will generate ARCs that target the KRAS and cMYC driver oncogenes and treat preclinical mouse models of lung cancer with combinations of ARCs to induce a "synthetic lethal" RNAi response that selectively kills the lung cancer cells based on their mutant genetics, while sparing normal cells. Looking at the big picture, the successful development of ARC RNAi delivery technology here has the potential to enable generating ARC RNAi therapeutics capable of selectively hitting all other driver oncogenes in lung cancer. |
