Anticancer Effects of a Repurposed Drug in Colon Cancer

项目摘要/摘要 大约25%-30%的确诊结肠癌(CC)没有发现局部或远处侵犯， 最终发展为转移性疾病，目前还没有治愈转移性疾病的方法。应答率 目前化疗的比例较低，约为20%。因此，这项研究涉及到改变药物的用途 Pimavanserin(PIMA)对CC的治疗至关重要。利用最初开发的现有药物的战略 对于另一种疾病，有望对癌症患者产生很大影响。同时从长远来看降低成本 和艰难的药物开发过程中，重新调整用途呈现出许多其他关键优势 关于已知的PK/PD、POSIGN、毒性和安全性。5-羟色胺(5-羟色胺、5-羟色胺)升高； 其受体在CC中的水平及其信号转导可能参与促进肿瘤的活性。然而，几乎没有 关于其作用机制是已知的。5-HT2A受体(5-HT2AR)选择性反向激动剂PIMA IS 广泛用于临床环境中治疗帕金森氏病精神病。作为5-羟色胺及其 受体5-HT2AR被认为参与促进细胞生长，其受体的表达是 在高处的胃肠道，我们询问了PIMA在抗癌活性中的作用。我们观察到 PIMA通过激活转化生长因子-β肿瘤抑制因子功能抑制CC细胞生长并诱导细胞凋亡。 拮抗5-羟色胺/5-羟色胺受体对bcl2家族蛋白和MEK/ERK的调节作用 发信号。有趣的是，我们对经PIMA处理的CC细胞的初步RNA-SEQ结果揭示了PIMA对 与细胞生长、细胞凋亡、转化生长因子/Smad和MEK/ERK信号转导相关的基因。我们最初的 实验表明，PIMA在体内同种异体移植模型中抑制肿瘤生长，且无毒性 效果。因此，这些研究提供了强有力的原则证明，即PIMA是一种有效的治疗剂 对CC有低毒作用。我们推测Pimavanserin在结肠中提供了有效的抗癌活性。 通过取消5-HT2AR及其受体的活性抑制细胞增殖和诱导细胞凋亡 与转化生长因子和MEK/ERK信号的串扰。在这里，我们建议(1)确定作用机制 PIMA在抑制肿瘤生长中的作用；(2)确定PIMA的抗癌作用及其机制 PIMA在CC中的作用，使用人源化的有机类化合物小鼠模型和自发遗传模型。 影响：虽然已经有几种化疗药物被引入用于CC的治疗，但它们仍然 充满副作用，范围有限，长期治疗失败。重新调整非癌症药物的用途 有效的抗癌活动对于促进患者获得新的治疗选择至关重要。皮马是 成功地用于帕金森氏症，但从未被探索用于实体肿瘤的治疗。 因此，首次尝试研究PIMA在CC中的抗癌新功能将具有广泛的应用前景 对抗结肠癌疗法发展的影响。这一探索性和临床前生物医学 这项研究与NCI特别感兴趣的两个优先研究领域(PAR-22-216)完美匹配。

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).