Roughly 500,000 cancer patients are treated with radiotherapy each year. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. These sequelae include proctitis, cystitis, esophageal stricture, cutaneous fibrosis plus others. We propose a novel means of preventing the acute and late radiation injury to normal tissues in these patients. Inhibitors of GSK-32 pathway can serve as radiation protective agents. Lithium can inhibit the GSK-32 pathway. Lithium-containing topical formulations are candidates for being effective radioprotectors by delivering the metal ion to the basal cell layer of epidermis (progenitor cells), preventing radio-induced apoptosis in normal cells in the skin overlying areas of radiation treatment. A total 12 prototype formulations will be screened in a radiation-induced injury porcine model. Six of the formulations will contain lithium succinate and the other six will contain lithium lactate. Two levels of the lithium salts will be screened (1% and 10%), each as an ointment, a gel, and an emulsion (cream). The best formulation(s) will be selected based on induction of proteins that enhance cell viability and inhibition of radiation-induced apoptosis. The efficacy and safety of selected formulations will be optimized in Phase II, supporting proof-of-concept for testing in humans and an IND submission to the FDA.
Public Health Relevance: Over 500,000 cancer patients are treated with radiotherapy each year, and there are presently 10,000,000 cancer survivors in the US. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. The goal of this proposal is to attenuate skin injury through development of a topical drug that markedly enhances the viability of the epidermis when administered before irradiation therapy to cancer patients undergoing targeted treatment of deeper tumors with radiation therapy.
Public Health Relevance Statement: Hallahan, Dennis E. PROJECT NARRATIVE Over 500,000 cancer patients are treated with radiotherapy each year, and there are presently 10,000,000 cancer survivors in the US. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. The goal of this proposal is to attenuate skin injury through development of a topical drug that markedly enhances the viability of the epidermis when administered before irradiation therapy to cancer patients undergoing targeted treatment of deeper tumors with radiation therapy.
Project Terms: Acute; Address; Affect; Animal Model; Animal Models and Related Studies; Animals; Antioncogene Protein p53; Apoptosis; Apoptosis Pathway; Apoptotic; Area; Attenuated; Basal Cell; Basal Layer; Biological; Body System, Dermatologic; Body Tissues; Bone Marrow; CREB; CREB1; CREB1 gene; Cancer Patient; Cancer Radiotherapy; Cancer Survivor; Carbonic acid, dilithium salt; Cell Death; Cell Death, Programmed; Cell Survival; Cell Viability; Cells; Cellular Tumor Antigen P53; Communities; Corium; Cream; Cutaneous; Cutis; Cystitis; Cytoprotectants; Cytoprotective Agent; Cytoprotective Drugs; DNA Damage Repair; DNA Repair; Data; Deglutition; Dermal; Dermis; Development; Dilithium Carbonate; Dose; Drug Administration, Topical; Drug Formulations; Drugs; Dysfunction; Emulsions; Endothelial Cells; Epidermis; Epithelial Cells; Epithelium; Esophageal Stenosis; Esophageal Stricture; Exhibits; Family member; Family suidae; Fibroblasts; Fibrosis; Formulation; Formulations, Drug; Functional disorder; Gel; Gene Family; Goals; Granulopoiesis; Hair Follicle; Hair follicle structure; Health; Hematopoietic; Human; Human, General; Hydrogen Oxide; In Vitro; Injury; Integument; Integumentary system; Ions; Ischemia; Late Radiation Injury; Lead; Leukocytopenia; Leukopenia; Li+ element; Lithium; Lithium Carbonate; Lithium Chloride; Lithium chloride (LiCl); Magnesium; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medication; Metals; Mg element; Mice; Modeling; Mother Cells; Murine; Mus; Names; Necrosis; Necrotic; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; Neutropenia; Normal Cell; Normal Tissue; Normal tissue morphology; Oils; Ointments; Oncoprotein p53; Organ System, Dermatologic; Outcome; Pain; Painful; Pathway interactions; Patients; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phosphatases; Phosphohydrolases; Phosphomonoesterases; Phosphoprotein P53; Phosphoprotein pp53; Phosphoric Monoester Hydrolases; Physiopathology; Pigs; Population; Prevention; Preventive; Proctitis; Progenitor Cells; Proliferating; Protective Agents; Protective Drugs; Protein TP53; Protein p53; Proteins; QOL; Quality of life; Radiation; Radiation Effect Modifiers; Radiation Injuries; Radiation Protectants; Radiation Protection; Radiation protector; Radiation therapy; Radiation-Protective Agents; Radiation-Protective Drugs; Radio; Radioprotection; Radioprotective Agents; Radioprotective Drugs; Radiotherapeutics; Radiotherapy; Recovery; Rete Malpighii; Reticuloendothelial System, Bone Marrow; Role; Safety; Salts; Salves; Series; Side; Site; Skin; Sodium Chloride; Sodium chloride (NaCl); Stem cells; Stratum Basale; Stratum Germinativum; Suidae; Surface; Swallowing; Swine; TP53; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Topical application; Tumor Protein p53; Unguents; Unscheduled DNA Synthesis; Water; Work; Wound Healing; Wound Repair; aqueous; base; biomarker; cell type; clinical efficacy; design; designing; drug candidate; drug/agent; efficacy testing; gene product; heavy metal Pb; heavy metal lead; improved; in vivo; inhibitor; inhibitor/antagonist; irradiation; keratinocyte; lithium succinate; model organism; necrocytosis; neuronal; novel; p53 Antigen; p53 Tumor Suppressor; pathophysiology; pathway; porcine; pre-clinical; preclinical; prevent; preventing; pro-apoptotic protein; prospective; prototype; public health relevance; radiation protection drug; ray (radiation); rectitis; rectum inflammation; salt; skin lesion; social role; success; suid; tissue repair; topical administration; topical drug application; topically applied; transcription factor; tumor; wound
