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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

基本信息

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
项目类别：
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

项目摘要

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).

项目总结/文摘