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AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway

The AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway represents a joint effort to encourage and support junior faculty who are in the first four years of a faculty appointment (at the start of the grant term) to conduct cancer research on the HER family pathway and establish successful career paths in this field. Proposed research projects are restricted to basic, translational, clinical, or epidemiological projects that substantially advance the field of cancer research on the HER family pathway.

2015 Grantee

Christine M. Lovly, MD, PhD
Assistant Professor of Medicine and Cancer Biology
Vanderbilt University Medical Center
Nashville, Tennessee
 Novel and therapeutically actionable EGFR rearrangements in lung cancer

The prospective identification and rational therapeutic targeting of tumor genomic alterations has revolutionized the care of patients with lung cancer, which is the leading cause of cancer related deaths in the United States and worldwide. In particular, activating mutations in the tyrosine kinase domain of the EGF receptor (EGFR) are found in 10-35% of lung adenocarcinomas, the predominant subtype of non-small cell lung cancer (NSCLC). Such mutations, which occur most commonly either as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to FDA-approved EGFR tyrosine kinase inhibitors (TKIs) and have enabled molecularly targeted therapy in this disease. Several large phase III clinical trials have shown that patients with advanced EGFR-mutant lung cancer derive superior clinical responses when treated with EGFR tyrosine kinase inhibitors (TKIs) as compared with standard-of-care chemotherapy. By analyzing the tumors of patients with lung cancer, we have identified two novel EGFR genomic alterations that have not previously been reported: EGFR exon 18-25 kinase domain duplication (EGFR-KDD) and EGFR c-terminal fusions. The principal objective of these studies is to define novel molecular cohorts of lung cancer characterized by the presence of these novel EGFR alterations. We will use an integrated approach incorporating genomics, proteomics, cell based methods, mouse models, and human tumor tissue to understand how EGFR-KDD and EGFR fusions deregulate EGFR signaling in lung tumors. These studies are expected to answer some fundamental questions regarding activation of the EGFR kinase and function of the EGFR C-terminal regulatory region. Findings from these studies will be immediately translatable as there are already several FDA approved EGFR inhibitors in clinical use.

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