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-19 (GRIM-19) by a genome-wide knockdown strategy. In our recent publication in the PNAS, we have shown that GRIM-19 gene is either suppressed or mutated in several human cancers, including those of head and neck, and a mono-allelic loss of Grim-19 in mice enhances susceptibility to tumorigenesis. We demonstrated that direct administration of naked plasmids carrying GRIM-19 or lentiviruses expressing GRIM-19 into tumors robustly suppressed tumor growth and metastases, indicating its potential therapeutic utility. However, as a viable commercial strategy, we will recombinantly express GRIM-19 containing a protein transduction domain (PTD) to develop a potent protein therapeutic (rGRIM-19) that could block cancer cell growth. The PTD domain allows transfer of protein across the cell membrane. We already produced rGRIM-19 and purified. In our preliminary studies, rGRIM-19 kills oral cancer cells, but not normal cells. Based on our compelling preliminary data we hypothesize that rGRIM-19 will prove to be an effective biological therapeutic for controlling tumor growth. To test this hypothesis, we will investigate the therapeutic utility of rGRIM-19 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- 19 KO mouse and also developed GRIM-19 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-19 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-19 on human tumors in vivo. At the end of this study we expect to develop a protein therapeutic for treating human tumors.
Public Health Relevance Statement: Project Narrative Head and neck Squamous cell carcinoma (HNSCC) is on the rise at annual rates from 4% to as much as 10% in recent years (600,000 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-19, a new tumor suppressor, in suppressing HNSCC.
Project Terms: Agreement; Animals; Antibodies; antitumor effect; Apoptosis; base; Biological Response Modifier Therapy; cancer cell; Cancer Cell Growth; cancer therapy; cell bank; Cell division; Cell membrane; cell motility; Cell Surface Receptors; Cells; Cessation of life; Cetuximab; Charge; Chronic Disease; Clinic; Clinical Research; Clinical Trials; Complex; conventional therapy; cytokine; Data; Defect; DNA; Drug Kinetics; Electron Transport; Epidermal Growth Factor Receptor; Exhibits; experimental study; Functional disorder; Future; Gene Mutation; Genes; genetic signature; Genome; genome-wide; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hormones; Human; Immune; in vivo; Interferons; Investigation; Investigational Drugs; Killings; knock-down; Knockout Mice; Legal patent; Licensing; Loss of Heterozygosity; malignant mouth neoplasm; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Missense Mutation; Modeling; Molecular; Mono-S; mortality; mouse model; Mouth Neoplasms; mouth squamous cell carcinoma; Mus; Mutate; Neoplasm Metastasis; novel; novel therapeutics; Oncogenic; Oral cavity; oral dysplasia; outcome forecast; Outcome Study; Papilloma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; phase 1 study; Phase I Clinical Trials; Plasmids; Point Mutation; preclinical study; Predisposition; Production; Property; Proteins; Publications; receptor; Recombinant Proteins; Recombinants; Retinoids; STAT3 gene; Subfamily lentivirinae; targeted treatment; Technology; Testing; Therapeutic; therapeutic protein; Time; Toxic effect; transcription factor; Treatment Efficacy; tumor; tumor growth; Tumor Suppressor Genes; Tumor Suppressor Proteins; tumorigenesis; United States; Vitamin A; Xenograft Model
