In the present submission we are requesting funding to support studies designed to assess proof-of-concept for a novel cell-based approach that possesses the potential to concurrently address multiple pathobiologic mechanisms initiated by chemo- + high dose irradiation. The importance of this effort is underscored by fact that oral mucositis is a common side effect of chemo- and radiotherapy especially in patients receiving head & neck radiation. More specifically, it has been estimated that nearly 40% of all patients treated with standard doses of chemotherapy experience some degree of mucositis while nearly all patients undergoing high-dose chemotherapy experience this debilitating side effect. Despite key advances, such as clinical guidelines and increased understanding of the molecular pathways leading to targeted therapeutics mucositis continues to represent an important medical need in many oncology patients especially with recently emergent molecularly targeted therapies that are causing unique toxicities of the mucosa. New approaches for this important toxicity are needed in order to set the stage for customized therapeutic approaches in future oncology practice. Our proposed approach involves the systemic application of mesenchymal stem cells (MSCs) genetically engineered to express recombinant extracellular superoxide dismutase (ECSOD-MSCs). Furthermore, we will assess the potential for increased efficacy following treatment of these cells with ASC-101 which has been shown to enhance the selectin-mediated homing of MSCs and other stem/progenitor cells to sites where selectins are upregulated in response to inflammation and tissue damage. Our preliminary studies show that mouse ECSOD-MSCs are more effective than MSCs at prolonging survival in mice following exposure to a lethal dose of radiation. We are proposing to expand on these positive results with studies using hamster MSCs genetically engineered to express ECSOD in an established hamster model of oral mucositis. In addition, we will assess the potential to enhance efficacy by treatment of these ECSOD-MSCs with ASC- 101. For our proof-of-concept studies we are proposing two specific aims: SA#1: Synthesis of ECSOD-MSCs SA#2: Examination of varying concentrations of control and ASC-101 treated ECSOD-MSCs in an established hamster model of oral mucositis. Positive results in these experiments will support our subsequent submission of an SBIR Phase II to further characterize this approach with human ECSOD-MSCs (dose response, time course, intermittent cisplantin/radiation dosing, etc) and for IND-enabling efforts leading to the eventual clinical application of our proposed therapeutic approach in patients with chemo/radiation-induced oral mucositis. With currently over 100 different clinical trials investigating MSCs in various indications, our presently proposed approach expands on these efforts with the exploration of the potential efficacy of genetically engineered MSCs in this indication in need of new therapy.
Thesaurus Terms: Address;Adverse Effects;Animal Model;Anti-Inflammatory;Anti-Inflammatory Agents;Area;Base;Bone Marrow;Cancer Center;Cancer Therapy;Cannulas;Cell Therapy;Cells;Cheek Structure;Chemotherapy;Clinical;Clinical Application;Clinical Trials;Collaborations;Cytokine;Dose;Ensure;Equilibrium;Experience;Exposure To;Extracellular;Funding;Future;Genes;Genetic Engineering;Genetically Modified Cells;Guidelines;Hamsters;Head And Neck Structure;High Dose Chemotherapy;Homing;Human;In Vivo;Inflammation;Inflammatory;Interruption;Intractable Pain;Intraperitoneal Injections;Irradiation;Laboratories;Left;Location;Mediating;Medical;Mesenchymal Stem Cells;Methodology;Modeling;Molecular;Mucositis;Mucous Membrane;Mus;Novel;Novel Strategies;Oncology;Oral Mucositis;Outcome Measure;Paracrine;Pathway Interactions;Patients;Phase;Phenotype;Primary Outcome;Protocols Documentation;Public Health Relevance;Publishing;Radiation;Radiation Therapy;Radio;Reaction Time;Reactive Oxygen Species;Recombinants;Research Design;Research Study;Response;Scientist;Selectins;Site;Small Business Innovation Research Grant;Solid Neoplasm;Staging;Stem;Stem Cells;Superoxide Dismutase;Techniques;Therapeutic;Therapeutic Agents;Therapeutic Target;Tissues;Toxic Effect;Transfection;Treatment Efficacy;
