An experimental issue hampering our ability to understand the therapeutic refractoriness of melanoma and other human cancers has been a lack of validated and faithful models for efficacy testing. Historically, promising anti-cancer compounds have been tested for preclinical efficacy in vitro and then in mouse 'xenograft'models prior to human testing. In xenograft systems, human cancer cell lines are grown under the skin of immunocompromised mice, and then xenograft-bearing animals are treated with intended therapies. These models are not physiologic, and have a poor track record of predicting therapeutic success. Recent changes have made it possible to test would-be cancer therapies in genetically engineered murine models (GEMMs) of cancer, which provide several advantages to xenograft models. Studies conducted in the UNC Mouse Phase I Unit (MP1U) have shown that testing in GEMMs can better replicate human pharmacokinetics and efficacy prediction, and results from these studies can provide timely data for clinical trials. In this proposal we will study the therapeutic efficacy of several novel anti-cancer drugs slated for human trials in patients with melanoma, using our credentialed GEMMs. We will chose for testing, regimens that are currently being testing in human clinical trials, including anti-immune system targeted therapeutics, which are not able to be tested in xenograft models. Through the use of several well selected and validated GEM models of melanoma harboring different 'driver'genetics, we will identify somatic events associated with response to specific therapeutic agents. Responding and refractory tumors will be tested using genomic analysis of RNA and DNA to provide a further understanding of therapeutic response. We will then compare the predicted efficacy of these agents in GEMMs to results from 12 ongoing or planned human clinical trials, to empirically determine the ability of these murine 'co-clinical'trials to predit efficacy in human patients with melanoma.
|Burd, Christin E; Liu, Wenjin; Huynh, Minh V et al. (2014) Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov 4:1418-29|