DF/HCC Program Affiliation

Translational Pharmacology and Early Therapeutic Trials
Lung Cancer

DF/HCC Associations

BIDMC, Lung, Clinical Trial Chairs

Research Abstract

(co-investigators: Daniel G. Tenen, MD and Susumu Kobayashi, MD, PhD)
Lung cancer is the leading cause of death from cancer in the United States. Better understanding of oncogenes and tumor suppressor genes involved in lung cancer hold the promise of improving clinical care of afflicted patients.
The transcription factors C/EBPalpha and Foxa2 play an essential role in airway epithelial differentiation, and are likely candidates in the pathogenesis of non-small cell lung cancer (NSCLC). Our group observed that many lung cancer cell lines have down-regulation of both C/EBPalpha and Foxa2 protein and mRNA, and hypothesized these transcription factors are novel tumor suppressor genes. We have started to correlate the immunohistochemical expression of C/EBPalpha and Foxa2 with pathological characteristics of primary lung tumors and the patients’ clinical outcomes. We also plan to identify the molecular mechanism of down-regulation of these genes, by studying if epigenetic or genetic changes are culprits. The last step of our project consists of testing compounds that can either re-establish C/EBPalpha-mediated pathways abrogated in NSCLC with special interest resides in the synthetic triterpenoids (CDDO and derivatives).
Another area of intense research by our laboratories is in the study of mechanisms of acquired resistance to gefitinib and erlotinib in EGFR-mutant NSCLCs and clinical response of patients with EGFR mutations to tyrosine kinase inhibitors (TKIs). Our group was one of the first to describe the T790M and L747S secondary resistant mutations. Current work will define a pharmacological response pattern of these T790M and non-T790M secondary mutations to established and novel EGFR inhibitors, with an aim of translating these findings into the clinic and ongoing clinical trials at the DFHCC for EGFR mutant patients that progress after gefitinib and erlotinib (such as DF-HCC 07-204 among others; trials are run in collaboration with Pasi Janne, Bruce Johnson, David Jackman, Thomas Lynch and Lecia Sequist).
We also have identified a key effector of TKI-induced apoptosis in the pro-apoptotic BH3-only peptide Bim. Efforts are underway on how to integrate these findings into clinical care of TKI-resistant patients.

Publications

• Costa DB, Li S, Kocher O, Feins RH, Keller SM, Schiller JH, Johnson DH, Tenen DG, Halmos B.Immunohistochemical analysis of C/EBPalpha in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: A correlative study of E3590.
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• Costa DB, Kobayashi S.Are exon 19 deletions and L858R EGFR mutations in non-small-cell lung cancer clinically different?.Br J Cancer 2007 Jan 29;96(2):399; author reply 400.
  17224926
• Costa DB, Dayaram T, D'Alo F, Wouters BJ, Tenen DG, Meyerson M, Tsao MS, Halmos B.C/EBPalpha mutations in lung cancer.Lung Cancer 2006 Aug;53(2):253-4.
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