Chemoprotectants for Head-Neck Therapeutics

口腔黏膜炎是化疗、放疗或化疗/放疗联合治疗的主要剂量限制和并发症副作用。它被认为是头颈癌治疗中最重要的并发症。口腔黏膜炎伴随着巨大的疼痛，并可能导致危及生命的并发症。喉癌治疗后的吞咽功能障碍会使人特别虚弱。化学保护剂的开发是本I期提案的中心目标。在初步研究中，Reaction Biology公司已经完成了三个独立的高通量筛选（HTS）活动，用于细胞存活的小分子调节因子。提出了三个具体目标：(1)在细胞培养中验证命中；(2) hit-to-lead化学计划，以推进最有前途的化学物质；（三）细胞系中化合物的放射线毒性试验。这些化合物将用于局部或直接注射，不需要传统的口服活性，因此可能在一定程度上偏离经典的Lipinsky和ADMET限制。由于化疗和放疗方法由于脱靶毒性而剂量有限，因此在癌症治疗期间使用细胞生存促进剂可能会给患者带来一些好处。

DESCRIPTION (provided by applicant): Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. The development of chemoprotectants is the central goal of this Phase I proposal. In preliminary studies, Reaction Biology Corporation has completed three separate high throughput screening (HTS) campaigns for small molecular regulators of cellular survival. Three specific aims are proposed: (1) validation of hits in cell culture; (2) hit-to-lead chemistry program to advance the most promising chemistries; and (3) testing of compounds in cell lines for radiotoxicity. Such compounds will be used topically or by direct injection and do not require traditional oral activity and therefore may deviate to some degree from classic Lipinsky and ADMET constraints. Since chemotherapy and radiotherapeutic approaches are dose-limited due to off-target toxicity, the use of cell survival promoting agents during cancer treatments may offer several benefits to patients. PUBLIC HEALTH RELEVANCE: Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. Even though apoptosis is considered the central theme in oral mucositis, little work with caspase inhibitors has been conducted to date. Reaction Biology Corp. has developed a few novel, potent and selective caspase inhibitors and would like to evaluate their cell death protection activities in radiation induced apoptosis assays. The potent chemoprotectants will be further optimized and evaluated in mice models in next phase study.