Since biologic events underlie clinical outcomes, we hypothesize that unraveling mechanisms of intracellular signaling and metastasis in lung cancers will lead to the identification of new targets for therapy for these illnesses and for individual patients. Our experience developing EGFR and ALK kinase inhibitors, and the discoveries that mutations in EGFR and KRAS and ALK- rearrangements underlie sensitivity and resistance to targeted therapies, have shown the practicality and potential of this approach. Our 4 research projects and 3 cores propose to continue a decade long iterative research process uniting clinical and laboratory observations. These efforts have linked genetic aberrations in tumors to outcomes in patients and identified agents targeting these same aberrations that benefit persons with lung cancers. This grant embraces investigators, technologies, and pathways, each focused by specific clinical questions, proposing to identify targets for therapies in lung cancers. Project 1 (Massagu) identifies mediators of metastasis and immune evasion that can serve as targets for intervention. Project 2 (Rosen) probes signaling in BRAF- and KRAS-driven lung cancers. Project 3 (Lovely) investigates mechanisms and modulators of sensitivity and resistance to EGFR and ALK kinase inhibitors. Project 4 (Lowe) uses mouse models and RNA interference to interrogate KRAS- driven lung cancers focusing on combinatorial strategies including the allele specific inhibitors studied in Project 2 and probing the impact of therapy-induced senescence on immune surveillance. Our Molecular Profiling and Pathology Core crystallizes more than a decade of experience in precise pathologic characterization, and use of the next-generation technologies for comprehensive molecular profiling of lung cancers. The Biostatistics and Bioinformatics Core ensures consistency in biostatistical analyses and provides projects and the Pathology Core with analytic capabilities for genomic data. The Administrative Core has created an organizational structure that assures integration and interaction by facilitating communication and dissemination of findings and providing a forum for the principal investigators, leaders, and the Executive and Scientific Advisory Committees to conduct scientific review and integration of new opportunities to accelerate progress.
Lung cancers are America?s leading cancer killers, responsible for 158,000 deaths this year. This grant addresses two of the most critical roadblocks to improving the care and curability of persons with these illnesses: understanding how cancers spread (metastasis) and the lack of medicines to prevent metastases or to eradicate cancers that have spread from the lungs.
|Yu, Helena A; Perez, Leslie; Chang, Qing et al. (2017) A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib. J Thorac Oncol 12:102-109|
|Ichihara, Eiki; Westover, David; Meador, Catherine B et al. (2017) SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer. Cancer Res 77:2990-3000|
|Yaeger, Rona; Yao, Zhan; Hyman, David M et al. (2017) Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. Cancer Res 77:6513-6523|
|Weigelt, Britta; Comino-Méndez, Iñaki; de Bruijn, Ino et al. (2017) Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer. Clin Cancer Res 23:6708-6720|
|Pal, Debjani; Pertot, Anja; Shirole, Nitin H et al. (2017) TGF-? reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells. Elife 6:|
|Yu, H A; Sima, C; Feldman, D et al. (2017) Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol 28:278-284|
|Boire, Adrienne; Zou, Yilong; Shieh, Jason et al. (2017) Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell 168:1101-1113.e13|
|Nieto, Patricia; Ambrogio, Chiara; Esteban-Burgos, Laura et al. (2017) A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548:239-243|
|Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S et al. (2017) Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548:234-238|
|Drilon, Alexander; Somwar, Romel; Wagner, Jacob P et al. (2016) A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer. Clin Cancer Res 22:2351-8|
Showing the most recent 10 out of 168 publications