The goal of this Project is to develop personalized therapeutic approaches for NSCLC patients based on tumor molecular profiles taken prior to treatment. Currently, molecularly-guided therapy for NSCLC patients is limited to the minority of patients with targetable oncogenic drivers (e.g. EGFR mutations) but the majority of patients to not have such alterations with matching drugs, and these markers to not inform the selection of chemotherapy or other treatments. This project will create a broadly useful classification for NSCLC patients using two approaches. Expression Clades (ECs), based on mRNA expression profiles, and Mutational Clades (MCs), based on DNA mutational alterations. We hypothesize that: 1) tumor ECs and MCs alone, or when combined together ("Genomic Clades", GCs), reveal underlying biologically distinct lung cancer subgroups with different therapeutic responses to targeted agents, chemotherapy and acquired vulnerabilities ("synthetic lethalities");2) clades may be used to predict treatment response and facilitate developing novel targeting strategies. Our preliminary data support these hypotheses as well as the feasibility of applying the clades to the clinic. The translational goals are to develop these clades as CLIA-certified "enrollment biomarkers" for such personalization and to study them in preclinical models, patient tumor specimens, and in a "window of opportunity" neoadjuvant trial. We have developed the following specific aims to bring this project to fruition.
Aim 1 : We will develop and refine our classification of ECs, MCs, and GCs using clinical and molecularly annotated data sets (e.g. TCGA Lung datasets, which we have profiled for a panel of protein markers), and apply the clades to our existing preclinical models including cell lines and xenograft models.
Aim 2. We will test and validate the association between clades and drug response for selected targeted agents (nintedanib, sorafenib) and chemotherapy regimens in preclincial in vitro and in vivo models, and identify novel clade-based targeting strategies and molecular vulnerabilities. Using this approach we have recently identified novel monogenic vulnerabilities for specific clades.
Aim 3. We will translate clades into the clinic by testing their value in predicting prognosis and benefit from adjuvant, chemotherapy, as well as treatment response to targeted agents (nintedanib and sorafenib) and nintedanib in combination with chemotherapy in the neoadjuvant trial. To do this we will leverage our existing SPORE Pathology Core resources, those from the completed BATTLE study, and those from this project's prospective "window of opportunity" neoadjuvant therapy trial. We have assembled a multidisciplinary team of laboratory and clinical investigators including collaborations with all ofthe SPORE Cores.
Success in this project would have a major impact in overcoming the barriers to biomarker-driven selection of therapies for individual NSCLC patients, by creating a new functional molecular classification of NSCLC directly tied to preclinical models, chemotherapy and targeted agent response patterns, and molecular vulnerabilities. This will lead to improved therapies, mechanistic insights into the differences between NSCLC subgroups, and will accelerate the integration of biomarker-selected therapies into clinical trials.
|Wen, Chi-Pang; Zhang, Fanmao; Liang, Dong et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clin Cancer Res 21:193-200|
|Chiappori, A A; Kolevska, T; Spigel, D R et al. (2015) A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol 26:354-62|
|Mender, Ilgen; Gryaznov, Sergei; Dikmen, Z Gunnur et al. (2015) Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. Cancer Discov 5:82-95|
|Kim, Eric S; Ye, Yuanqing; Vaporciyan, Ara A et al. (2015) Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study. J Thorac Oncol 10:302-8|
|Fujimoto, Junya; Wistuba, Ignacio I (2014) Current concepts on the molecular pathology of non-small cell lung carcinoma. Semin Diagn Pathol 31:306-13|
|Ludlow, Andrew T; Robin, Jerome D; Sayed, Mohammed et al. (2014) Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res 42:e104|
|Lin, Steven H; Wang, Jing; Saintigny, Pierre et al. (2014) Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. BMC Genomics 15:1079|
|Yang, Yanan; Ahn, Young-Ho; Chen, Yulong et al. (2014) ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. J Clin Invest 124:2696-708|
|Holohan, Brody; Wright, Woodring E; Shay, Jerry W (2014) Cell biology of disease: Telomeropathies: an emerging spectrum disorder. J Cell Biol 205:289-99|
|Osborne, Jihan K; Guerra, Marcy L; Gonzales, Joshua X et al. (2014) NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas. Mol Biol Cell 25:1782-92|
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