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SPORE UPDATE Fred R. Hirsch, MD, PhD Lung Cancer SPOREs University of Texas South Western/ M.D. Anderson Cancer Center John Minna, Jack Roth Johns Hopkins University Stephen Baylin University of Colorado Paul Bunn Vanderbilt University David Carbone University of Pittsburgh Jill Siegfried Dana Farber/Harvard Cancer Institute Bruce Johnson H. Lee Moffitt Cancer Center Gerold Bepler/Eric Haura Lung Cancer SPOREs Selected Highlights • Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non-Small Lung Cancer Predict for Response to TKIs (DFHCC, UCHSC) • 3p21.3 Tumor Suppressor FUS1-mediated Molecular Therapy for Lung Cancer (UTSW/MDACC) • Lung Cancer Proteomics (Vanderbilt U., U. Pittsburgh, UCLA, U Colorado) • Methylation Markers in Lung Cancer (JHU, UCHSC) • Estrogen Receptor-Targeted Therapy in Lung Cancer (U. Pittsburgh) • Lung Cancer Biomarkers and Chemoprevention Consortium EGFR MUTATIONS AND OTHER MARKERS: Discovery and Implications Lung Cancer SPOREs involved: Dana Farber Harvard Cancer Center (Bruce Johnson, PI) University of Colorado (Paul Bunn, PI) UT Southwestern/MD Anderson CC (John Minna, PI) Vanderbilt University (David Carbone, PI) 2004 2005 EGFR mutations in non-small cell lung carcinomas predict response to tyrosine kinase inhibitors (TKIs) (Science, 304:1497, 2004; N Engl J Med, 350:2129,2004) EGFR gene copy number by FISH: a molecular predictor for response to TKIs (J Natl Cancer Inst, 97:643, 2005) Aberrant EGFR signaling and enhanced sensitivity to EGFR inhibitors in lung cancer (Cancer Res, 65:226, 2005) (N Engl J Med, 352:786, 2005) 2007 MET amplification leads to TKI resistance in lung cancer by activating ERBB3 signaling (Science, 316:1039, 2007) Ethnic differences in polymorphisms, mutations, and amplification of the EGFR gene (PLoS Med, 4:125, 2007) Serum-based marker predicts responses to EGFR inhibitors (VeriStrat®; J Natl Cancer Inst 99:846, 2007) 2009 2011 Novel mutant-selective EGFR kinase inhibitors against EGFR T790M (Nature, 462:1070, 2009) Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors (Science Transl Med, 3:75ra26, 2011) Univ. of Colorado Lung Ca. SPORE 2011: 4 new or redesigned projects • Project 1: The FGFR signal pathway in lung cancer especially of squamous histology. F. Hirsch, MD, PhD (applied) and L. Heasley, PhD (basic). Collaborators: Drs. Camidge, Wynes, biostat • Project 2:Improving Outcomes from EGFR and ALK TKIs. P. Bunn, MD (applied), J. DeGregori, PhD (basic). Collaborators: Drs. Doebele, Camidge, Chan, Helfrich, Casias, Franklin, Aisner, biostat • Project 3: Role of eicosanoids in the development of lung cancer. R. Nemenoff, PhD (basic), M. Geraci, MD and R. Keith, MD (applied) Collaborators: Drs. Winn, Tennis, Merrick • Project 4: Biomarkers of lung cancer risk and early detection. Y. Miller, MD (applied), H. Wolf, MPH (population science), F. Hirsch, MD, PhD (basic)Collaborators: Drs. Varella-Garcia, Mascaux, Wynes, Franklin, Merrick Chromosomal Aneusomy by FISH in sputum in Lung Cancer Cases and Controls. % Abnormal Sensitivity Specificity cases controls (95% CI) (95% CI) Within 12 Mo (n =89) 77.7 4.5 0.78 (0.63, 0.89) 0.95 (0.85, 0.99) >12-18 Mo (n =35) 66.7 15 0.67 (0.38, 0.88) 0.85 (0.62, 0.97) >18-24 Mo (n =33) 56.2 0 0.56 (0.30, 0.80) 1.00 (0.80, 1.00) >24 Mo (n =108) 44.4 11.3 0.36 (0.24, 0.50) 0.89 (0.77, 0.96) Latency PGI2 Signaling Pathways Fatty Acid Arachidonate O-P-O-X (polar head group) PLA2 Free Fatty Acid COX 1 Constitutive COX 2 Inducible PGH2 PGIS PGI2 PGIR Gs AC Other signaling pathways (PPAR) cAMP Biological Response Background: Prostaglandin levels are high in normal lung and and low in NSCLC Normal Lung NSCLC Cell Lines PGI2 3,450 ng/g 333 ng/g PGE2 430 ng/g PGI2 Synthase PGH2 PGE2 11,952 ng/g Synthase PGIS present PGIS absent Survival Time (Months) Prostacyclin synthase levels are prognostic. Histology of Bronchial Squamous Epithelium Normal (Grade 1) Squamous Metaplasia (Grade 3) Mild Dysplasia (Grade 4) 74% in baseline bronch Moderate Dysplasia (Grade 5) Severe Dysplasia (Grade 6) Carcinoma in situ (Grade 7) Iloprost Chemoprevention Trial: Primary Results Iloprost Placebo Tools for the Identification and the Detection of Biomarkers in Clinical Samples and Patients • • • • • Nodule Clinic (Denver CO) Lung Nodule and/or Dysplasia Exhaled Breath Clinical Investigation (Invasive for all) 2 years of follow-up till final validation Specify the unique VOCs signature for each of the subtypes of LC 1.SCLC 2.NSCLC Adenocarcinomas Squamous cell carcinomas Large cell carcinoma Dr. Nir Peled (MD, PhD) Tel Aviv Univesity http://cancergrace.org/lung/2010/04/05/an-introduction-to-lung-cancer/ NSCLC SCLC Pancreas H460 H526 Mia Paca Calu3 H187 Panc H1435 H69 S3.6 H4006 H774 H1975 A549 H820 H1650 (a) (b) Compounds Totally Released NSCLC SCLC Compounds Totally Consumed Abundance [%] 0.0 Diethyl Phthalate Acetophenone Isopropyl Myristate Decanal Dodecane Nonanal Butylated Hydroxytoluene Hexadecane 1-Heptanol, 4-methylAzacyclotridecan-2-one Benzene, 1,3-bis(1,1-dimethylethyl)Tridecane, 2-methylDodecane, 2-methylDodecane, 4-methylTridecane, 3-methylTridecane, 6-methyl1-Hexene, 3,4-dimethylDodecane, 3-methyl- Undecane, 2,4-dimethylTridecane, 5-methylTetradecane, 5-methylTridecane, 4-methylPentanenitrile, 2,2,4-trimethyl2-methyl-, 1-(1,1-dimethylethyl)-2-methyl-1,3-pro Dodecanoic acid, 1-methylethyl ester Propanenitrile, 2,2'-azobis[2-methylAcetic acid, octyl ester Nonane, 5-propylUndecane, 3-methylTetradecane, 2-methyl1-Heptanol, 6-methylBenzenesulfonamide, N-butylCyclopentane, pentyl5-Methyl-1-heptanol Undecane, 2,6-dimethylDodecane, 5-methylTetradecane, 3-methylDodecane, 5,8-diethylTetradecane, 4-methylTridecane, 7-methylDodecane, 2,6,11-trimethyl1-Hexanol, 5-methyl-2-(1-methylethyl)-, acetate Dodecane, 2,5-dimethylTridecane, 2,5-dimethyl(S)-(+)-5-Methyl-1-heptanol 0.5 Abundance [%] NSCLC SCLC 0.0 Ethylbenzene Benzene, 1,3-dimethyl- Furan, tetrahydro- Decane 1-Hexanol, 2-ethyl- Octanal 0.5 1.0 Benign Nodules Age (years) Active Smokers Never Smokers PY (Total) Nodule Existence Nodule Size (cm) Histology Stage (N=29) 61.5 ± 6.4 10 (35%) 3 (10%) 44.3 ± 33.3 21 (72%) 1.86±1.1 Non-Cancerous Dysplasia/Hyperplasia Infectious/Inflammation Carcinoid Malignant Nodules 13 9 5 2 (N=53) 64.9 ± 7.2 19 (36%) 8 (15%) 40.5 ± 27.0 53/53 (100%) 2.7±1.7 NSCLC: 47 Adenocarcinoma 30 Squamous 13 Large Cell 2 Poorly Diff. 2 SCLC 6 NSCLC: Stage I / II 23 / 4 Stage III / IV 10 / 10 SCLC: Limited / Ext 3 / 3 P-value (<0.05) NS NS NS NS NS Malignant/ Benign SCLC/NSCLC Sensitivity Specificity Accuracy PPV NPV 76.2-87.9 83.3-88.2 78.8-88.0 88.9-93.5 66.7-78.9 75 96.56 93.93 96.6 75.0 (A) (B) DANA-FARBER • Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. • To understand the exact mechanism of the drug resistance acquisition in NSCLC patients treated with EGFR inhibitors, the investigators analyzed tumor biopsies from patients at the time they acquired resistance. The disease underwent various courses: in some patients the resistance gateway mutation T790 appeared, in others amplification of the MET tyrosine kinase receptor occurred; another group of patients developed new patterns of resistance with the amplification of the EGFR gene and mutations of PIK3CA gene. In a few patients, lung cancers transitioned from epithelial to mesenchymal (more aggressive) morphology or they converted from the non-small cell lung cancer phenotype to small cell lung cancer. The genetic and histological analysis provides new insights into drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development of drug resistance. (Sci Transl Med) - PMID: 21430269 Johns Hopkins SPORE • Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells • Histone deacetylase inhibitors have potential as chemotherapeutic agents, however their mechanism of action are not completely understood. In this work we demonstrate that histone deacetylase inhibitors lead to downregulation of the CHK1 kinase. These results define a pathway through which Chk1 inhibition can mediate HDACi-induced mitotic entry and cell death and suggest that Chk1 could be an early pharmacodynamic marker to assess HDACi efficacy in clinical samples (PLoS One) - PMCID: PMC3001870 • http://www.ncbi.nlm.nih.gov/pubmed/21179472 UNIVERSITY OF PITTSBURGH • Combined Analysis of Estrogen Receptor b-1 and Progesterone Receptor Expression Identifies Lung Cancer Patients with Poor Outcome • A better understanding of the role and interaction of hormone and growth factor pathways in the lung is necessary to elucidate novel effective preventative and treatment strategies for lung cancer. This work examined the combined effect of expression of estrogen receptor b-1 and progesterone receptor in tissues from lung cancer patients and the influence of expression of other markers including the epidermal growth factor receptor and aromatase on patient survival. The correlations between expression of these markers and their combined influence on patient survival suggest that phenotyping these interacting markers together in lung cancer patients may better predict survival and suggest which patients could be candidates for hormonal therapy for lung cancer treatment. (Clin Cancer Res) - PMID: 21062926 http://www.ncbi.nlm.nih.gov/pubmed/21062926 VANDERBILT • A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer • The identification of somatically acquired tumor mutations is increasingly important in the clinical management of cancer because the sensitivity of targeted drugs is related to the genetic makeup of individual tumors. Thus, mutational profiles of tumors can help prioritize anticancer therapy. We report herein the development and validation of two multiplexed assays designed to detect in DNA from FFPE tissue more than 40 recurrent mutations in nine genes relevant to existing and emerging targeted therapies in lung cancer. These robust, reliable, and relatively inexpensive • assays should help accelerate adoption of a genotype-driven approach in the treatment of lung cancer. (J Mol Diagn) - PMID: 21227397 http://www.ncbi.nlm.nih.gov/pubmed/21227397 • Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases • In this surgical series, 52 resected lung adenocarcinomas from never-smokers ( 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes: EGFR, KRAS, ALK, HER2. ( J Clin Oncol) - PMCID: PMC2974342 http://www.ncbi.nlm.nih.gov/pubmed/20855837 • SWOG Task Force: Interactions with SPOREs, Cancer Centers & Other Groups