Anticancer Effects of a Repurposed Drug in Colon Cancer

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PROJECT SUMMARY/ABSTRACT About 25–30% of confirmed colon cancers (CC) without detectable local or distal invasion will eventually develop metastases, and there is currently no cure for metastatic disease. The response rates of current chemotherapy are low, around 20%. Therefore, this study related to repurposing a drug Pimavanserin (PIMA) for CC therapy is crucial. The strategy of using existing drugs originally developed for another disease, promises to have high impacts on cancer patients. While reducing costs in the long and difficult process of drug development, repurposing presents a number of other pivotal advantages regarding known PK/PD, posology, toxicity, and safety. Elevated serotonin (5-HT, 5-hydroxytryptamine), and its receptor levels in CC, and their signaling may be involved in promoting oncogenic activities. However, little is known regarding the mechanism of action. 5-HT2A receptor's (5-HT2AR) selective inverse agonist PIMA is widely used in the clinical setting for treatment of Parkinson's disease psychosis. As serotonin and its receptor 5-HT2AR have been suggested to be involved in cell growth promotion, and the receptor expression is high in gastrointestinal tract, we inquired about the role of PIMA in anticancer activities. We have observed that PIMA inhibits CC cell growth and induces apoptosis by activating TGF-ß tumor suppressor functions and antagonizing the effects of serotonin/5-HT2AR on the regulation of BCL-2 family proteins and MEK/ERK signaling. Interestingly, our initial RNA-seq results from CC cells treated with PIMA reveal the regulation of genes related to cell growth and apoptosis, and to TGF-ß/Smad and MEK/ERK signaling. Our initial experiments indicate that PIMA inhibits tumor growth in an in vivo allograft model (syngeneic) with no toxic effects. Therefore, these studies provide a strong proof-of-principle that PIMA is an effective therapeutic agent with low toxicity for CC. We hypothesize that Pimavanserin proffers its potent anti-cancer activities in colon cancer by inhibiting cell proliferation and inducing apoptosis through abrogating the activity of 5-HT2AR and its crosstalk with TGF-ß and MEK/ERK signaling. Here we propose to (1) determine the functional mechanisms of action of PIMA in suppressing tumor growth, and (2) determine the anti-cancer efficacy and mechanism of action of PIMA in CC using a humanized mouse model with organoids and a spontaneous genetic model. Impact: Although several chemotherapeutic agents have been introduced for the treatment of CC, they are still fraught with side effects, limited scope, and long-term treatment failure. Repurposing non-cancer drugs with potent anti-cancer activities is crucial to facilitate patient access to new treatment options. PIMA is successfully used for Parkinson's disease, but it has never been explored in the treatment of solid tumors. Therefore, this first attempt of investigating the novel anticancer functions of PIMA in CC will have a broad impact on the development of anti-colon cancer therapies. This exploratory and preclinical biomedical research perfectly matches with two priority research areas of specific interest of NCI (PAR-22-216).