Molecular Therapeutics Theme 2 Accomplishments

Theme 2: Identify cellular/molecular determinants and clinically relevant biomarkers of treatment response on which to base therapy

Scientific Accomplishments 

Drs. Bepler, Gadgeel, A Schwartz, and Cote, working with Dr. Bollig-Fischer, identified “driver” mutations in non-small cell lung cancer (NSCLC) in African American and European American patients using the Sequenom MassArray system and a multiplexed panel for 214 oncogenic mutations in 26 genes previously identified in NSCLC. African Americans with NSCLC exhibited multiple genetic mutations more frequently than European Americans with a different mutation profile. These results provided impetus for CAP/CLIA certification of the Genomics Core in 2013 for use of custom panels for lung cancer oncogenes and amplifications/deletions.

  • Lead researchers - Drs. Bepler, Gadgeel, and Bollig-Fischer
  • Collaborative researchers - Drs. Schwartz and Cote

Dr. Ratnam, working with Drs. Gadgeel, Shields, Matherly, and Bepler, demonstrated the role of glucocorticoid receptor (GR) status as a determinant of the variability in the sensitivity of non-small cell lung cancer (NSCLC) cells to pemetrexed (PEM), a S-phase-targeted drug in front-line or maintenance therapy  of advanced NSCLC, generally administered with dexamethasone (Dex). Their results predict that in non-squamous NSCLC, S-phase suppression by Dex, combined with a reduction in PEM transport, attenuates responsiveness to PEM and that GR status is an important determinant of tumor variability of this response.  Based on these in vitro results, an investigator-initiated clinical trial (Shields, Lead PI; Ratnam, Gadgeel, Heilbrun, collaborators) is enrolling NSCLC patients who will be screened by RT-PCR for high levels of GRα, then imaged with FLT-PET to test the hypothesis that Dex will decrease S-phase progression, as reflected in decreased activity of thymidine kinase-1.

  • Lead researchers - Drs. Ratnam. Gadgeel, Shields, Matherly and Bepler.
  • Collaborative researcher - Dr. Heilbrun

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