GRIM for head and neck cancer therapy

Project Summary Many clinical and preclinical studies demonstrated that interferons IFNs exert a superior anti tumor effect when combined with retinoids a class of vitamin A metabolites We identified a novel tumor suppressor Gene associated with Retinoid IFN induced Mortality GRIM by a genome wide knockdown strategy In our recent publication in the PNAS we have shown that GRIM gene is either suppressed or mutated in several human cancers including those of head and neck and a mono allelic loss of Grim in mice enhances susceptibility to tumorigenesis We demonstrated that direct administration of naked plasmids carrying GRIM or lentiviruses expressing GRIM into tumors robustly suppressed tumor growth and metastases indicating its potential therapeutic utility However as a viable commercial strategy we will recombinantly express GRIM containing a protein transduction domain PTD to develop a potent protein therapeutic rGRIM that could block cancer cell growth The PTD domain allows transfer of protein across the cell membrane We already produced rGRIM and purified In our preliminary studies rGRIM kills oral cancer cells but not normal cells Based on our compelling preliminary data we hypothesize that rGRIM will prove to be an effective biological therapeutic for controlling tumor growth To test this hypothesis we will investigate the therapeutic utility of rGRIM for treating tumors in a relevant mouse model of head and neck squamous cell carcinoma HNSCC For this purpose we have generated a conditional Grim KO mouse and also developed GRIM deficient patient derived xenograft PDX models We will use the KO mice to generate oral tumors and determine if treatment of these tumors with rGRIM would reverse the oncogenic gene signatures and enforce tumor growth suppression in vivo A similar approach will be taken with the PDX models to study the effect of rGRIM on human tumors in vivo At the end of this study we expect to develop a protein therapeutic for treating human tumors Project Narrative Head and neck Squamous cell carcinoma HNSCC is on the rise at annual rates from to as much as in recent years new cases worldwide Targeted therapeutic drug such as cetuximab anti EGFR antibody has only limited effect underscoring an urgent need of new therapeutics This proposal will investigate the therapeutic utility of recombinant GRIM a new tumor suppressor in suppressing HNSCC