Cachexia-anorexia syndrome is a life-threatening aspect to many diseases, in particular many forms of cancer or therapies for cancer. The obvious symptoms of this disease include lack of appetite, and a loss of lean body mass disproportionate to the reduction in caloric intake. However, the less obvious effects of cachexia include multi-organ failure, due to high metabolic rate-induced apoptosis (programmed cell death). The economic costs of cachexia are huge. The National Cancer Institute estimates that up to 40% of cancer deaths are directly due to cachexia, and it is likely a factor in a significant percent of other cancer fatalities. Cachexia is a component in the pathology of many other diseases. Hyperactivity of the central melanocortin (MC) system appears to be a common factor in most, if not all, forms of cachexia We designed and synthesized a MC drug-like peptide (TCMCB07), using a new platform technology that makes peptides into therapeutic agents with an extended in vivo half-life. TCMCB07 produced a reversal of cachexia in an aggressive experimental cancer model; restoring food intake and lean body mass. The ability of TCMCB07 to enhance weight gain has been confirmed in large animal models. Preliminary safety testing has shown that the drug is relatively free of cardiovascular, blood chemistry or hematological side-effects. The goals of this application are to perform the required preclinical experiments to establish the relative safety and efficacy of our anticachexia therapeutic, and define its interactions with cellular transport systems. Delineating the transport system(s) for TCMCB07 will allow a determination of its potential interaction with other clinically relevant drugs. The overall objective of these experiments is the submission of an Investigative New Drug application to the FDA for an anticachexia drug, a required step before Phased Clinical Trials. Preventing or reversing cachexia has the potential to enhance the efficacy of current and future anticancer agents, as well as be an important therapeutic component in the treatment of many other life-threatening diseases.
Public Health Relevance Statement: Gruber, Kenneth A. Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. We developed orally anti-cachexia MC drugs, and confirmed their safety and efficacy in small animal trials. The project is now proceeding into the formal stages of FDA review.
Project Terms: Acute; Adverse effects; analog; Animal Model; Animal Testing; Animals; Anorexia; Anticachexia Agent; Antineoplastic Agents; Antiviral Agents; Apoptosis; base; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Chemical Analysis; Body Fluids; Cachexia; cancer cachexia; Cancer Model; cancer radiation therapy; cancer therapy; Canis familiaris; Cardiovascular system; Cessation of life; Chronic; Clinical Trials; clinically relevant; Collaborations; commercialization; Communicable Diseases; Complication; Contractor; Contracts; Cyclic GMP; Cyclic Peptides; Data; design; Desire for food; Detection; Development; Disease; Dose; drug development; Drug Interactions; Eating; economic cost; Energy Intake; Epithelial; Etiology; Feces; Fluorescence; Food Energy; Food Intake Regulation; Funding; Future; Goals; good laboratory practice; Half-Life; High Pressure Liquid Chromatography; Homeostasis; Hour; Human; Hyperactive behavior; in vivo; Inflammatory; inhibitor/antagonist; Investigational Drugs; Isomerism; lean body mass; Licensing; Life; Link; Liver; Malignant Neoplasms; Measures; Mediation; melanocortin receptor; Membrane Transport Proteins; Metabolic; metabolic rate; Methods; Michigan; Modeling; Monitor; Morbidity - disease rate; mortality; National Cancer Institute; novel therapeutics; Oral; Organ failure; Parents; Pathology; peptide drug; Peptide Transport; Peptides; Performance; Pharmaceutical Preparations; Phase; Plasma; Play; pre-clinical; prevent; Regulatory Affairs; renal tubular reabsorption; research study; Rodent; Role; Safety; safety testing; Sampling; Serological; Small Business Innovation Research Grant; solute; Staging; Structure; success; Symptoms; Syndrome; System; tandem mass spectrometry; Technology; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transmembrane Transport; Transport Process; Universities; uptake; Urine; Validation; Weight Gain
