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GRIM19 for head and neck cancer therapy

GRIM19 用于头颈癌治疗

基本信息

批准号：
9408784
负责人：
DHAN V. KALVAKOLANU
金额：
$ 29.85万
依托单位：
GLYCOMANTRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408784
关键词：
Agreement Animals Antibodies Apoptosis Biological Response Modifier Therapy Cancer Cell Growth Cell Surface Receptors Cell division Cell membrane Cells Cessation of life Cetuximab Charge Chronic Disease Clinic Clinical Research Clinical Trials Complex DNA Data Defect Drug Kinetics Electron Transport Epidermal Growth Factor Receptor Exhibits Functional disorder Future Gene Mutation Genes Genome Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Hormones Human Immune Interferons Investigation Investigational Drugs Knockout Mice Legal patent Licensing Loss of Heterozygosity Malignant Neoplasms Metastatic Neoplasm to Lymph Nodes Missense Mutation Modeling Molecular Mono-S Mouth Neoplasms Mus Mutate Neoplasm Metastasis Oncogenic Oral cavity Outcome Study Papilloma Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase I Clinical Trials Plasmids Point Mutation Predisposition Production Property Proteins Publications Recombinant Proteins Recombinants Retinoids STAT3 gene Subfamily lentivirinae Technology Testing Therapeutic Time Toxic effect Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins United States Vitamin A Xenograft Model antitumor effect base cancer cell cancer therapy cell bank cell motility conventional therapy cytokine experimental study genetic signature genome-wide in vivo killings knock-down malignant mouth neoplasm mortality mouse model mouth squamous cell carcinoma novel novel therapeutics oral dysplasia outcome forecast phase 1 study preclinical study receptor targeted treatment therapeutic protein transcription factor tumor tumor growth tumorigenesis

项目摘要

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-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.

项目总结