PROJECT SUMMARY/ABSTRACT Pancreatic cancer is one of the deadliest cancers in the US, at a 5-year survival rate of ~11%. One of the hallmarks of this cancer are the driver mutations, which include KRAS and p53 mutations. Mutations of p53, a tumor suppressor, causes the tumor to become more invasive and chemoresistant. Moreover, a major contributor of morbidity of pancreatic cancer patients, is cachexia, which is defined as an involuntary loss in muscle and fat deposits. Cachexia is a devastating syndrome which affects about 80% of pancreatic cancer patients and increases mortality and decreases quality of life. Most cachectic patients don’t qualify for chemotherapy and if they do, they are refractory to them. Currently, cachexia is treated in the clinic with nutritional supplements and appetite stimulants. However, there are no FDA-approved therapies for cachexia yet. Our preliminary data implicated Perp, to be a potential target in the tumor and muscles in PDAC. We utilized age- appropriate murine models of cancer and cachexia and observed Perp, a known p53 target gene, to be increased in PDAC tumors. Further, we observed that inhibition of Perp decreased tumor proliferation/burden. Expression of Perp demonstrated to be negatively correlated to patient survival. Moreover, patients with mutant p53, also had an increased expression of Perp as compared to patients with wildtype p53.Inhibition of Perp in p53 mutant tumors increased downstream p53 signaling targets, implying possible activation of p53-associated pathways. Furthermore, we also observed increased expression of Perp in cachectic muscles, which decreased upon preventing muscle loss. Subsequently, we also demonstrated increased expression of Perp to be an early event in cancer conditioned-media mediated myotube atrophy. In this study, we will investigate the differential role of Perp in tumor progression and chemoresistance in mutant p53 compared to wildtype p53 tumors. Next, we will utilize genetic tools and murine models to target Perp in the muscles in vivo. The overarching goals of the first two aims are to establish Perp as an efficient target in the tumor and muscle. In silico modeling of Perp provided a list of compounds with binding affinities to two predicted binding sites of Perp. We shortlisted compounds which were successful in decreasing tumor burden and rescuing muscle atrophy in vitro. In the third aim, we will further characterize/modify these molecules for specificity, toxicity and stability and test them in preclinical models of PDAC and cachexia. Development of novel therapies which have the potential to decrease tumor burden and rescue muscle wasting will be beneficial in improving patient survival, chemotherapy tolerance and quality of life.

Project Narrative Pancreatic cancer is the third highest cause of cancer-related deaths and about 80% of pancreatic cancer patients suffer from cachexia, which is a debilitating syndrome contributing to increased mortality and decreased efficiency of chemotherapy. We illustrate a common target, Perp, in the tumor and muscles, which when inhibited has the potential to abrogate tumor proliferation and muscle loss upon inhibition. The overarching aim of this study is to elucidate the role of Perp in cancer and cachexia and develop novel inhibitors against Perp.