Anticancer Effects of a Repurposed Drug in Colon Cancer

一种新用途药物对结肠癌的抗癌作用

• 批准号: 10728673
• 负责人: PRAN K DATTA
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728673
• 关键词: Agonist; Allografting; Apoptosis; Area; BCL1 Oncogene; Biomedical Research; Cancer Cell Growth; Cancer Patient; Cell Survival; ChIP-seq; Clinical; Colon Carcinoma; Colonic Neoplasms; Data; Development; Disease; Distal; Drug Kinetics; Exhibits; Gastrointestinal tract structure; Gene Expression Profile; Gene Expression Regulation; Genetic Models; Growth; Human; In Vitro; Induction of Apoptosis; Inhibition of Cell Proliferation; Invaded; MEKs; Mediating; Medical; Modeling; Molecular; Morphology; Mus; Neoplasm Metastasis; Normal Cell; Oncogenic; Organ; Organoids; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Probability; Process; Protein Family; Psychoses; Regulation; Research Priority; Role; Safety; Serotonin; Serotonin Receptor 5-HT2A; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; Structure; Therapeutic; Therapeutic Agents; Tissue-Specific Gene Expression; Toxic effect; Transforming Growth Factor beta; Treatment Failure; Tumor Suppressor Proteins; Tumor-Derived; anti-cancer; anticancer activity; cancer cell; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; colon cancer cell line; colon cancer treatment; cost; drug development; drug repurposing; experimental study; humanized mouse; in vivo; interest; migration; mouse model; novel; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; receptor; receptor expression; response; serotonin receptor; side effect; therapeutically effective; transcriptome sequencing; translational potential; tumor; tumor growth; tumor initiation; tumor progression

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).

项目概要/摘要 约 25-30% 的确诊结肠癌 (CC) 没有可检测到的局部或远端浸润 最终发生转移，目前尚无治愈转移性疾病的方法。回复率 目前化疗的比例较低，约为 20%。因此，这项研究涉及药物的重新利用 匹马范色林 (PIMA) 对于 CC 治疗至关重要。使用最初开发的现有药物的策略 对于另一种疾病，有望对癌症患者产生很大影响。在长期降低成本的同时 以及药物开发的困难过程，重新利用具有许多其他关键优势 关于已知的 PK/PD、剂量学、毒性和安全性。血清素升高（5-HT、5-羟色胺），以及 CC 中的受体水平及其信号传导可能参与促进致癌活性。然而，很少 关于作用机制是已知的。 5-HT2A受体（5-HT2AR）选择性反向激动剂PIMA是 临床上广泛用于治疗帕金森病精神病。由于血清素及其 受体5-HT2AR已被认为参与细胞生长促进，该受体的表达量为 由于PIMA在胃肠道中含量较高，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 TGF-β 肿瘤抑制功能抑制 CC 细胞生长并诱导细胞凋亡 拮抗 5-羟色胺/5-HT2AR 对 BCL-2 家族蛋白和 MEK/ERK 调节的影响 发信号。有趣的是，我们对用 PIMA 处理的 CC 细胞进行的初步 RNA 测序结果揭示了 与细胞生长和凋亡以及 TGF-β/Smad 和 MEK/ERK 信号传导相关的基因。我们最初的 实验表明，PIMA 在体内同种异体移植模型（同基因）中抑制肿瘤生长，且无毒性 影响。因此，这些研究提供了强有力的原理证明，证明 PIMA 是一种有效的治疗剂 对CC毒性低。我们假设 Pimavanserin 在结肠中具有有效的抗癌活性 通过消除 5-HT2AR 及其活性来抑制细胞增殖并诱导细胞凋亡，从而抑制癌症 与 TGF-ß 和 MEK/ERK 信号传导的串扰。这里我们建议（1）确定功能机制 PIMA在抑制肿瘤生长方面的作用，以及（2）确定其抗癌功效和机制 使用具有类器官的人源化小鼠模型和自发遗传模型研究 PIMA 在 CC 中的作用。 影响：虽然已经推出了几种化疗药物来治疗 CC，但它们仍然 充满副作用、范围有限且长期治疗失败。重新利用非癌症药物 有效的抗癌活性对于促进患者获得新的治疗选择至关重要。 PIMA 是 成功用于治疗帕金森病，但从未在实体瘤的治疗中进行探索。 因此，研究 PIMA 在 CC 中的新型抗癌功能的首次尝试将具有广泛的应用前景。 对抗结肠癌疗法的发展产生影响。这种探索性和临床前生物医学 研究与 NCI (PAR-22-216) 特别感兴趣的两个优先研究领域完美匹配。