Preclinical assessment of a novel compound for treating radiation-induced oral mucositis

治疗放射性口腔粘膜炎的新型化合物的临床前评估

基本信息

批准号：
10480609
负责人：
Colton Joseph Lloyd
金额：
$ 31.83万
依托单位：
SINOPIA BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480609
关键词：
ADME Study Acute Animal Model Animals BRD2 gene Binding Biological Process Biological Sciences Bromodomain Cancer Prognosis Cell Line Clinic Clinical Clinical Trials Data Development Dose Drug Kinetics Esophagus Evaluation FDA approved Follow-Up Studies Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Transcription Government Hamsters Health Care Costs Healthcare Systems Inflammation Intravenous Lead Learning Licensing Machine Learning Malignant Neoplasms Measures Modeling Mucositis Mucous Membrane Mus Oncology Oral Oral Administration Oral cavity Outcome Pain Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Physicians Pilot Projects Preclinical Testing Process Property Protein Family Proteins Publishing Radiation Radiation therapy Safety Schedule Secure Severities Solid Neoplasm Supportive care Systems Biology Tertiary Protein Structure Testing Therapeutic Time Toxicology Ulcer Work base cancer therapy cell type chemotherapy clinical candidate commercialization common treatment computational platform cost fractionated radiation gastrointestinal head and neck cancer patient healing in vivo inhibitor insight interest keratinocyte growth factor mouse model novel novel therapeutics oral mucositis phase 2 study pre-clinical pre-clinical assessment prevent profiles in patients side effect small molecule success tumor growth wound healing

项目摘要

Project Summary Inflammation and ulceration of mucosal tissue, called mucositis, is a severe side effect of many common treatments in oncology, including chemo- and radiotherapy. Mucositis development is costly to the health care system and can lead to poorer outcomes for patients. Mucositis of the mouth and esophagus, called oral mucositis, is particularly common in head and neck cancer patients receiving radiation therapy, where roughly 80% of patients develop this side effect. Treating oral mucositis remains a large clinical unmet need with no FDA approved treatments for patients with solid tumors. Using Sinopia Biosciences’ computational platform, we identified a unique target class and an associated small molecule for preventing and/or treating mucositis. The target class has an established safety profile in patients with solid tumors. In two studies with the acute radiation- induced hamster model of oral mucositis, we observed promising results that oral administration of the compound significantly decreased the duration of ulcerative mucositis and in some animals completely prevented the development of ulcers. The observed effect size was as large or larger than other compounds currently in the clinic tested in the same model. The test compound is a pan-inhibitor of several targets in the target class, each with multiple binding domains. In this Phase I proposal, we will test three additional compounds with different selectivity to these targets and domains in order to understand the pharmacology of this target class to determine the target that most contributes to mucositis amelioration. If successful, in Phase II of this proposal we will develop a novel compound selective for the most effective target. We will then characterize this new compound in the fractionated radiation model of oral mucositis and the chemotherapy-induced gastrointestinal mucositis to advance towards the clinic.

项目概要粘膜组织的炎症和溃疡，称为粘膜炎，是许多常见药物的严重副作用。肿瘤治疗，包括化疗和放射治疗，对医疗保健来说是昂贵的。系统，并可能导致患者口腔和食道粘膜炎（称为口腔炎）的预后较差。粘膜炎在接受放射治疗的头颈癌患者中尤其常见，其中大约 80% 的患者会出现这种副作用，在没有 FDA 批准的情况下，治疗口腔粘膜炎仍然是一个巨大的临床未满足需求。使用 Sinopia Biosciences 的计算平台，我们批准了针对实体瘤患者的治疗方法。确定了用于预防和/或治疗粘膜炎的独特靶标类别和相关小分子。在两项针对急性放射的研究中，目标类别已确定对实体瘤患者的安全性。在诱导仓鼠口腔粘膜炎模型中，我们观察到口服该化合物的有希望的结果显着缩短溃疡性粘膜炎的持续时间，并且在某些动物中完全预防了溃疡性粘膜炎的发生观察到的效果大小与目前使用的其他化合物一样大或更大。在同一模型中进行临床测试，测试化合物是目标类别中多个目标的泛抑制剂。具有多个结合域。在第一阶段提案中，我们将使用不同的化合物测试另外三种化合物。对这些靶标和域的选择性，以便了解该靶标类别的药理学，从而确定如果成功，我们将在该提案的第二阶段中确定最有助于改善粘膜炎的目标。开发一种针对最有效靶标的新型化合物，然后我们将表征这种新化合物。在口腔粘膜炎的分次放射模型和化疗引起的胃肠道粘膜炎中向诊所前进。