Mechanisms and Therapeutics in Cancer Anorexia/Cachexia

[unreadable] DESCRIPTION (provided by applicant): The anorexia/cachexia syndrome occurs in greater than 50 percent of patients with advanced cancer. The investigators propose a 2-pronged approach to dissect the pathophysiology of this debilitating syndrome: palliation of anorexia and abrogation of lean tissue wasting. First, they hypothesize that inhaled neuropeptide y (NPY) palliates anorexia, presumably by means of NPY-G protein receptor interactions. Since their preliminary data suggest circulating concentrations of this potent orexigenic hormone are depressed in anorexic cancer patients, they propose to launch a clinical trial in NPY. Second, they hypothesize that the TNFalpha inhibitor, etanercept, suppresses the ubiquitin-proteasome system -- a TNFalpha-driven pathway of muscle wasting -- and thereby allows cancer patients to regain lean tissue. The investigators propose to test whether etanercept leads to decreased muscle ubiquitin conjugates and preservation of lean tissue in advanced cancer patients. The specific aims of this proposal emphasize this 2-pronged approach to the cancer anorexia/cachexia syndrome at the levels of intake and lean tissue wasting and include: 1) To determine a non-toxic, biologically active dose of intranasal NPY. Such knowledge would lay the groundwork for larger clinical trials with this hormone in anorexia in cancer. 2) To explore whether NPY1 and Y5 receptor polymorphisms are associated with aneroxia in patients with advanced cancer independent of serum NPY. 3) To explore whether the TNFalpha inhibitor, etanercept, blocks the development of muscle ubiquitin-protein conjugates, preserves lean tissue and improves appetite. Such a trial would provide the scientific underpinnings for the investigation of cytokine blockade in the treatment of the cancer anorexia/cachexia syndrome. [unreadable] [unreadable] The principal investigator, Dr. Aminah Jatoi, has unique dual training in medical oncology and nutrition. This K23 grant application will serve as a springboard to allow her to delve into the pathophysiology of this syndrome and to develop into an independent clinical investigator.