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Name(s): Blake Smith and Vickram Gidwani

Name(s): Blake Smith and Vickram Gidwani High School(s): Oceanside High School, Oceanside, NY and Horace Mann School, Bronx, NY Mentor: Dr. Goutham Narla Project Title: Using Novel Small Molecule Derivatives to Treat Chemoresistant Lung Adenocarcinoma.

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Name(s): Blake Smith and Vickram Gidwani

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  1. Name(s): Blake Smith and Vickram Gidwani High School(s): Oceanside High School, Oceanside, NY and Horace Mann School, Bronx, NY Mentor: Dr. Goutham Narla Project Title: Using Novel Small Molecule Derivatives to Treat Chemoresistant Lung Adenocarcinoma Chemoresistance to anti-EGFR based therapies invariably develops in all metastatic lung cancer patients through mutations in the epidermal growth factor receptor (EGFR) and/or its downstream targets, PI3K/AKT and Ras/ERK. The FDA-approved typical antipsychotic, Trifluoperazine (TFP), has been shown to downregulate AKT activity and induce spontaneous apoptosis. Yet, the anti-dopaminergic properties of this class of drugs result in dose-limiting toxicities, making it less ideal for use in patients suffering from advanced cancers. The aim of this current study was to design novel derivatives from two structurally related neuroleptics, TFP and Chlorimipramine (CIP), which could decouple their toxic central nervous system side effects from their anti-cancer properties for clinical use in the treatment of TKI-resistant lung cancer. Based upon a preliminary screen of over twenty novel small molecules, we have identified two noteworthy derivative compounds, DBK-368 and DBK-382, in which we have successfully decoupled their anti-dopaminergic effects from their anti-proliferative properties and demonstrated that their mechanism of action is through simultaneous inhibition of AKT and ERK phosphorylation, in vitro and in vivo. In conclusion, these novel small molecules may prove to be promising monotherapies for the treatment of chemoresistant lung cancer.

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