Pamela Hershberger, Ph.D.

Institution: Health Research Incorporated, Roswell Park Cancer Institute Division

Project: Reversing Drug Resistance in EGFR Mutant Lung Cancers

Grant(s): Lung Cancer Discovery Award

EGFR mutant lung cancers are diagnosed in nearly 250,000 individuals worldwide each year. These cancers are treated using drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs). Although initially effective, almost all tumors stop responding to treatment in 1.5 years. In an increasing number of cases, EGFR TKIs stop working because tumors undergo a process termed the epithelial-mesenchymal transition (EMT). Our studies test a novel approach to reverse EMT and restore tumor sensitivity to EGFR TKIs. Our approach uses a protective shell or nanoparticle (NP) to deliver vitamin D (VD) and a drug called CTA091 to EGFR mutant tumors. Once inside tumor cells, VD reverses EMT. CTA091 prevents tumors from destroying VD, thus sustaining therapeutic benefit. The proposed studies will establish the safety and activity of our NP in combination with EGFR TKIs in lung tumor models, including patient avatars. Positive results will provide a solution to the problem of EMT-mediated drug resistance.

Update:

Over the past 8 months, we have been able to reproducibly synthesize the nanoparticles; demonstrate that they bind and are taken up by EGFR mutant lung cancer cells; demonstrate the superior activity of the intact nanoparticles versus component parts; and demonstrate that our novel nanoparticles significantly increase the sensitivity of EGFR mutant lung cancer cells to standard of care treatment with EGFR tyrosine kinase inhibitors. Future studies are designed to establish nanoparticle activity in a series of independent pre-clinical models we developed (including novel patient models) for scientific rigor and test for efficacy in mice.

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