A major component in the development / progression of lung cancer is loss of the tumor suppressor genes, E-cadherin and the secreted semaphorin, SEMA3F. We originally identified the SEMA3F gene and reported that its downregulation in patient samples correlates with advanced-stage disease. SEMA3F potently inhibits tumor cells in vitro and in vivo, and has additional anti-angiogenic effects on endothelial cells, where NRPs function as co-receptors for VEGF. Recently, we found that SEMA3F causes downregulation of activated avp3 integrin in tumor cells with loss of phospho-ERK, AKT and STATS, and inhibitory effects on HIF and VEGF. This results, at least in part, from inhibition of integrin-linked kinase and SRC. SEMA3F is a large molecule, which presently limits its therapeutic potential, However, based on our knowledge of semaphorin signaling, the use of small molecule and antibody inhibitors should allow mimicking of the SEMA3F effect. Downregulation of E-cadherin and SEMA3F occurs most commonly by silencing from transcriptional repressers, particularly ZEB1 and Snail. The molecular changes induced by transcriptional repressers are responsible for the epithelial-mesenchymal transition (EMT), which underlies the invasive / metastatic nature of many epithelial cancers. We've shown that E-cadherin loss correlates with poor outcome in lung cancer patients. Not only is ZEB1 responsible for E-cadherin loss, but it also suppresses SEMA3F, and confers resistance to EGFR inhibitors. This work has resulted in two ongoing lung cancer trials of erlotinib plus the HDAC inhibitor, SAHA (Vorinostat), and erlotinib plus celecoxib. Our current studies are focused on: 1) recapitulating the effects of SEMA3F by small molecules and antibodies with the goal of developing an effective therapeutic strategy, 2) identifying new targets of ZEB and Snail that contribute to the pathogenesis / progression of lung cancer and resistance to EGFR inhibitors and, 3) identifying the timing and frequency of EMT during lung cancer development, its relationship to other signal pathways (including SEMA3F) and, importantly, its clinical relevance in human lung cancers and premalignant lesions. We will also test the hypothesis that pre-malignant lesions with EMT are more likely to develop cancer or more aggressive tumors. If confirmed, these lesions may be responsive to treatment with HDAC inhibitors. The translational goals of Project 1 are highlighted by the use of preclinical data to design ongoing clinical trials with SPORE biomarker support, and plans for a new clinical trial also supported by SPORE biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058187-16
Application #
8117219
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
16
Fiscal Year
2010
Total Cost
$380,544
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Noonan, Sinead A; Patil, Tejas; Gao, Dexiang et al. (2018) Baseline and On-Treatment Characteristics of Serum Tumor Markers in Stage IV Oncogene-Addicted Adenocarcinoma of the Lung. J Thorac Oncol 13:134-138
DeHart, David N; Fang, Diana; Heslop, Kareem et al. (2018) Opening of voltage dependent anion channels promotes reactive oxygen species generation, mitochondrial dysfunction and cell death in cancer cells. Biochem Pharmacol 148:155-162
Patil, Tejas; Smith, Derek E; Bunn, Paul A et al. (2018) The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib. J Thorac Oncol 13:1717-1726
Suda, Kenichi; Kim, Jihye; Murakami, Isao et al. (2018) Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions. J Thorac Oncol 13:1496-1507
Helfrich, Barbara A; Gao, Dexiang; Bunn Jr, Paul A (2018) Eribulin inhibits the growth of small cell lung cancer cell lines alone and with radiotherapy. Lung Cancer 118:148-154
Kleczko, Emily K; Heasley, Lynn E (2018) Mechanisms of rapid cancer cell reprogramming initiated by targeted receptor tyrosine kinase inhibitors and inherent therapeutic vulnerabilities. Mol Cancer 17:60
McCoach, Caroline E; Le, Anh T; Gowan, Katherine et al. (2018) Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-small Cell Lung Cancer. Clin Cancer Res 24:3334-3347
Drilon, Alexander; Laetsch, Theodore W; Kummar, Shivaani et al. (2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378:731-739
Pilling, Amanda B; Kim, Jihye; Estrada-Bernal, Adriana et al. (2018) ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. Oncotarget 9:8823-8835
Kwak, Jeff W; Laskowski, Jennifer; Li, Howard Y et al. (2018) Complement Activation via a C3a Receptor Pathway Alters CD4+ T Lymphocytes and Mediates Lung Cancer Progression. Cancer Res 78:143-156

Showing the most recent 10 out of 435 publications