Novel therapeutics for targeting checkpoint dysfunction in cancer

针对癌症检查点功能障碍的新疗法

基本信息

批准号：
9232389
负责人：
FANG-TSYR LIN
金额：
$ 36.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232389
关键词：
Affect Apoptosis Binding Biochemical Biological Assay Breast Cancer Cell Bromodeoxyuridine Bypass Canes Cell Cycle Checkpoint Cell Cycle Progression Cells Chloroquine Complement DNA biosynthesis DNA replication fork Data Defect Drug resistance Event Functional disorder Goals Grant Knowledge Lead Malignant Neoplasms Malignant neoplasm of ovary Melanoma Cell Molecular Conformation Molecular Target Mus Mutation Normal Cell Nutrient Patients Protein p53 Proteins Quantitative Reverse Transcriptase PCR Recruitment Activity Replication Initiation SKBR3 Serum Structure TP53 gene Testing Therapeutic Therapeutic Intervention Toxic effect Transcription Regulatory Protein Translating Work Xenograft Model base calcein AM cancer cell cancer therapy cytotoxic design drug sensitivity gain of function in vivo inhibition of autophagy inhibitor/antagonist innovation intestinal epithelium malignant breast neoplasm mutant new therapeutic target novel novel therapeutics response screening small molecule inhibitor success synergism targeted treatment tumor

项目摘要

Proper checkpoint activation is necessary to temporarily halt cell cycle progression when cells are in nutrient-deprived conditions or encounter insults. These safeguard mechanisms are universally lost in cancer cells; nevertheless, some causes for the checkpoint perturbation in cancer remain to be investigated. In addition, it remains a challenge to translate our knowledge in this field into practical cancer therapy. The main goal of this project is to develop novel therapeutics aiming at cancer checkpoint perturbation. In this proposal, first we will study how certain hotspot mutations of tumor suppressor p53 actively inhibit the checkpoint response. Second, we will determine whether some mutant p53 directly promotes DNA replication, and if so, by what mechanism(s). Third, we will identify small molecule inhibitors targeting these molecular events. Lastly, we propose a “synthetic targeted therapy” strategy and leverage our new findings with the existing knowledge for cancer therapy. In our preliminary study, we have identified several lead inhibitors targeting this event. With the aid of one lead inhibitor we have obtained proof-of-concept to support feasibility of the proposed concept. In short, the proposed study will elucidate novel mechanisms of checkpoint perturbation and translate our discoveries into new therapeutics for a broad range of cancers.

适当的检查点激活对于暂时停止细胞周期进程是必要的细胞处于营养匮乏的状态或遭受侮辱。然而，癌细胞中普遍丧失了某些机制；此外，癌症中的检查点扰动仍有待研究。将我们在这一领域的知识转化为实际的癌症治疗的挑战。该项目的目标是开发针对癌症检查点的新疗法在这个提议中，首先我们将研究肿瘤的某些热点突变是如何发生的。其次，我们将确定p53抑制因子主动抑制检查点反应。某些突变体 p53 是否直接促进 DNA 复制，如果是，通过什么途径第三，我们将确定针对这些分子的小分子抑制剂。最后，我们提出了“综合靶向治疗”策略并利用我们的新疗法。在我们的初步研究中，我们根据现有的癌症治疗知识得出了这一结论。在一种先导药物的帮助下，已经确定了几种针对该事件的先导抑制剂。抑制剂我们已经获得了概念验证来支持所提出的可行性简而言之，拟议的研究将阐明检查点的新机制。扰动并将我们的发现转化为广泛的新疗法癌症。