Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 20% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cancer cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake, stimulates the release of growth hormone, increases muscle mass, and reduces markers of inflammation. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 30 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies completed during SBIR Phase I address each of these issues, resulting a long-acting ghrelin derivative that could be dosed subcutaneously once every other day in rats to reverse the effects of cachexia in the Yoshida rat model. The studies proposed in this Phase II application will investigate the ability of our long- acting ghrelin to ameliorate cachexia in two additional models. Methods for cGMP production of the long-acting ghrelin will be put in place. We will perform IND-enabling GLP toxicity and immunogenicity studies using the cGMP material. These studies are needed prior to beginning human trials. Once fully developed, this long- acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patients with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).
Public Health Relevance Statement: Cancer is often coupled with a serious condition called cachexia or involuntary weight loss. Studies have shown that cancer patients who have cachexia often respond poorly to chemotherapy, are at a greater risk of infection and have a reduced life expectancy. Currently there is no effective way to treat cachexia. The work described in this proposal will help develop treatments for cachexia based on a hormone made by the body that increases appetite and stimulates muscle growth. Relieving the symptoms of cachexia will significantly improve a cancer patient's quality of life and decrease the need for hospitalizations, resulting in reduced healthcare costs.
Project Terms: absorption; acyl group; Address; Amino Acids; Animal Model; Animals; Anorexia; Anti-inflammatory; Anti-Inflammatory Agents; appetite loss; Appetite Stimulants; base; Biological Markers; Biological Sciences; Body Weight; Body Weight decreased; Cachexia; cancer cachexia; Cancer Patient; Canis familiaris; Cessation of life; cGMP production; chemotherapy; Chronic Disease; Chronic Obstructive Airway Disease; Clinic; Clinical; clinical candidate; college; Complex; Congestive Heart Failure; Consumption; Coupled; Cyclic GMP; Data; deacylation; Development; Dose; Drug Kinetics; Eating; efficacy testing; Energy Intake; Enzyme-Linked Immunosorbent Assay; Fatigue; Fatty acid glycerol esters; FDA approved; food consumption; ghrelin; Growth; Half-Life; Health Care Costs; Home environment; Hormones; Hospitalization; Human; Immune response; immunogenicity; improved; increased appetite; Infection; Inflammatory; inflammatory marker; Intravenous infusion procedures; Laboratories; Lead; lean body mass; Life Expectancy; Limb structure; Malignant Neoplasms; Manufacturer Name; manufacturing process; Measures; Medicine; Methods; Modeling; Modification; Muscle; muscle form; Myocardium; outcome forecast; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Plasma; Process; Property; Pump; Quality of life; Rattus; receptor binding; reduce symptoms; reduced muscle mass; Regimen; response; Risk; Rivers; Rodent Model; scale up; Self-Administered; skeletal muscle wasting; Small Business Innovation Research Grant; Somatotropin; Staging; subcutaneous; Syndrome; Testing; Therapeutic Effect; Therapeutic Uses; Time; Toxic effect; Toxicokinetics; Toxicology; Weight; Weight Gain; Work
