The recent identification of recurrent genetic alterations in specific cancer genes has led, through biological and biochemical analyses, to new molecularly-targeted therapies for lung cancer that have shown promise in the clinic. Still, while genomic studies continue to identify lesions of potential therapeutic relevance to cancer, functional studies, which are historically slow, are required to validate these as potential targets and develop strategies to exploit them for therapeutic benefit. Among the most prominent genomic alterations occurring in NSCLC are point mutations leading to RAS oncoprotein activation, mutation and chromosomal losses involving the p53 tumor suppressor locus on chromosome 17p, and large deletions affecting the short arm of chromosome 8 (8p). These alterations have been known for many years and often occur in the same tumors, yet precisely how they contribute to lung cancer development and how they can be exploited remains unknown. The goal ofthis project is to understand the biological and mechanistic impact of KRAS, p53, and 8p alterations on the initiation and maintenance of lung cancer, and to initiate efforts to exploit their alteration for therapeutic purposes. The project's co-investigators have a history of collaboration and collective expertise in tumor suppressor genes, mouse modeling, and drug resistance mechanisms. Here they will apply genomic information obtained from human lung cancers to inform functional studies in mice, exploiting innovative technologies to characterize biological impact of known and novel lesions on lung carcinogenesis. Building on substantial preliminary data, the project will study effectors that are required for tumor maintenance in EGFR and KRAS driven lung cancers (alone and in combination with targeted drugs), explore the action of p53 in RAS limiting lung carcinoma development, and begin to characterize new genetic lesions that drive lung carcinogenesis. The project imports new mouse models and technologies into the program, and interacts with, and benefits from, each ofthe other projects and cores. Successful completion ofthe proposed work will provide a critical foundation for improving prognostic tools and developing new targeted therapeutic strategies with new agents or drug combinations.
Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This project addresses the two critical roadblocks to improving the care and curability of persons with lung adenocarcinomas: (1) understanding how adenocarcinomas spread to the brain (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung.
|Chen, Qing; Boire, Adrienne; Jin, Xin et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493-8|
|Hames, Megan L; Chen, Heidi; Iams, Wade et al. (2016) Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancerâ˜†. Lung Cancer 92:29-34|
|Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18|
|Lito, Piro; Solomon, Martha; Li, Lian-Sheng et al. (2016) Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351:604-8|
|Malladi, Srinivas; Macalinao, Danilo G; Jin, Xin et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165:45-60|
|Konduri, Kartik; Gallant, Jean-Nicolas; Chae, Young Kwang et al. (2016) EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discov 6:601-11|
|Dragani, Tommaso A; Castells, Antoni; Kulasingam, Vathany et al. (2016) Major milestones in translational oncology. BMC Med 14:110|
|Manchado, Eusebio; Weissmueller, Susann; Morris 4th, John P et al. (2016) A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534:647-51|
|Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582|
|MassaguÃ©, Joan; Obenauf, Anna C (2016) Metastatic colonization by circulating tumour cells. Nature 529:298-306|
Showing the most recent 10 out of 157 publications