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.
|Akbay, Esra A; Kim, James (2018) Autochthonous murine models for the study of smoker and never-smoker associated lung cancers. Transl Lung Cancer Res 7:464-486|
|Zhang, Wei; Girard, Luc; Zhang, Yu-An et al. (2018) Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 7:32-49|
|Tan, Xiaochao; Banerjee, Priyam; Liu, Xin et al. (2018) The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J Clin Invest 128:1267-1282|
|McMillan, Elizabeth A; Ryu, Myung-Jeom; Diep, Caroline H et al. (2018) Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer. Cell 173:864-878.e29|
|Walser, Tonya C; Jing, Zhe; Tran, Linh M et al. (2018) Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells. Cancer Res 78:1986-1999|
|Skoulidis, Ferdinandos; Goldberg, Michael E; Greenawalt, Danielle M et al. (2018) STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 8:822-835|
|Zhou, Xiaorong; Padanad, Mahesh S; Evers, Bret M et al. (2018) Modulation of Mutant KrasG12D -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function. Mol Cancer Res :|
|Ferdosi, Shadi; Rehder, Douglas S; Maranian, Paul et al. (2018) Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, ?1-4 Branching, ?1-6 Branching, and ?2-6 Sialylation in Cancer. J Proteome Res 17:543-558|
|Pietanza, M Catherine; Waqar, Saiama N; Krug, Lee M et al. (2018) Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 36:2386-2394|
|Abrams, Zachary B; Zucker, Mark; Wang, Min et al. (2018) Thirty biologically interpretable clusters of transcription factors distinguish cancer type. BMC Genomics 19:738|
Showing the most recent 10 out of 1059 publications