Dr. Daniel Costa of Beth Israel Deaconess Medical Center (a teaching hospital of Harvard Medical School) received the 2012 LCFA/IASLC Grant in Translational Lung Cancer Research. Dr. Costa has received the $300,000.00 two-year grant, to study Non-Small Cell Lung Cancer (NSCLC) patients with different EGFR mutations. Dr. Costa and his team are evaluating these selected patients for sensitivity and resistance to EGFR tyrosine kinase inhibitors (TKIs) to determine a genotype-response correlation.
Dr. Costa, a native of Brazil, received his MD from University of Sao Paulo’s Faculdade de Medicina de Ribeirao Preto and his PhD from State University of Campinas. He has been on staff at Beth Israel Deaconess Medical Center since 2004. Dr. Costa is conducting his research in conjunction with co-investigator Dr. Susumu Kobayashi (a laboratory scientist and translational cancer biology researcher) who has been his collaborator since 2005.
Regarding his research study for which he received the LCFA/IASLC funding, Dr. Costa says, “This project has the ability to significantly impact the care of the approximately 40,000 patients diagnosed with EGFR mutated NSCLC yearly in the United States. Our characterization of these specific EGFR mutations will lead to – in the short-term – a significant shift in patient care, since it will define which mutated tumors can reap the known palliative and survival benefits of approved EGFR treatments. The overall objective of our combined work is to maximize the chances that our results are applicable to care of patients with EGFR mutated NSCLC and that our findings eventually will lead to improvements in quality and quantity of life.”
A decade ago oncologists lumped together all non-small-cell lung cancers (NSCLCs) as a single disease and treated them with similar ineffective regimens. Molecular discoveries in the last several years have made it abundantly clear that NSCLCs that look similar are molecularly diverse, and the differences from one tumor type to another are vast.
In 2004, epidermal growth factor receptor (EGFR) mutations were identified in tumors from approximately 15%-20% of patients with NSCLC (more than 200,000 patients a year worldwide). This finding proved not merely scientifically interesting; it also changed clinical practice. Patients whose tumors harbored EGFR mutations experienced remarkable palliative improvement when they took oral drugs such as gefitinib, erlotinib or afatinib (i.e., kinase inhibitors), which block the kinase domain of the EGFR protein and are now approved for tumors that carry these mutations. However, not all EGFR mutations are predictive of response to EGFR inhibitors and in specific EGFR exon 20 insertions (the third most common type of EGFR mutations) constitute the majority of insensitive mutations.
Our group is focused in studying why EGFR exon 20 insertion mutations are different than other EGFR mutations and on how to develop novel treatment strategies for tumors that harbor these changes. To understand the patterns of resistance to EGFR inhibitors of EGFR exon 20 insertion mutations, in the first phase of the LCFA grant period, our research team generated the most extensive preclinical database of representative mutations using in vitro systems, structural models and NSCLC cell lines with these specific EGFR mutations.
With the support of the LCFA grant, we now understand the basic structure of the most prevalent EGFR exon 20 insertion mutations and why drugs like gefitinib, erlotinib and afatinib are unable to inhibit these mutations. We have further showed that all classes of EGFR inhibitors that in in clinical development are unable to inhibit common EGFR exon 20 insertion mutations. To circumvent the lack of precision therapies for this important group of recalcitrant lung cancers, we hope our expanding research tools will be used to identify novel therapies that function as precision therapies for EGFR exon 20 insertion mutated lung cancers.