Targeting vulnerabilities of therapy-resistant cancer cell states with small molecules

用小分子靶向治疗耐药的癌细胞状态的脆弱性

基本信息

批准号：
10227768
负责人：
STUART L SCHREIBER
金额：
$ 119.61万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227768
关键词：
Advanced Malignant Neoplasm Apoptosis Cancer Model Cancer cell line Cells Characteristics Clinical Collaborations Combined Modality Therapy Communities Computing Methodologies Data Data Set Dependence Disease remission Drug resistance Embryo Enzymes Gene Expression Profile Genetic Genetic study Immunologics Immunotherapy Learning Lipid Peroxides Lipids Malignant Neoplasms Mesenchymal Methods Oncology Pathway interactions Pharmaceutical Preparations Phase Regimen Resistance Sequential Treatment Surveys Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Visualization software algorithmic methodologies base cancer cell cancer therapy cancer type chemotherapy computerized tools large datasets novel overtreatment resistance mechanism response sarcoma small molecule small molecule inhibitor targeted treatment therapy resistant tool treatment response

项目摘要

ABSTRACT Targeted therapies and immunotherapies are two of the most transformative and promising advances in cancer treatment over the last two decades. Yet they, like conventional chemotherapies, frequently succumb to the ability of cancers eventually to resist therapeutic attacks on their vulnerabilities, reversing the initially impressive clinical responses to these treatments. This project focuses on conserved non-mutational mechanisms of resistance that are frequently encountered in resistance arising in multiple therapeutic regimens across multiple cancer types. In the current phase of the CTD2 Network, we developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities. The method relies on the Cancer Therapeutics Response Portal (CTRP), which houses a large dataset of quantitative compound sensitivity data and has been made available without restriction. Using CTRP, we found evidence for the existence of at least one such common therapy-resistant state, associated with mesenchymal characteristics of cancer cells. Importantly, this state emerges from treatment with either chemotherapy or targeted therapeutics across several cancer types. This project aims to fully dissect this pathway, and to discover other such pathways, to understand the bases of resistant-state vulnerabilities, and to learn how to exploit them therapeutically in a safe and effective way.

抽象的有针对性的疗法和免疫疗法是最具变革性和有希望的两种进步在过去的二十年中，癌症治疗。然而，它们像常规的化学疗法一样，经常屈服于癌症最终抵抗对其脆弱性的治疗攻击的能力，最初扭转了对这些治疗的令人印象深刻的临床反应。该项目侧重于保守的非矿化在多种治疗中引起的抗性中经常遇到的抗性机制多种癌症类型的方案。在CTD2网络的当前阶段，我们开发了功能强大的新使社区能够识别新型癌症脆弱性的工具和能力。该方法依赖于癌症治疗响应门户（CTRP），该门户拥有大量的定量化合物数据集灵敏度数据已无限制。使用CTRP，我们找到了证据至少存在一种这种常见的耐药状态，与间充质特征有关癌细胞。重要的是，该状态从化学疗法或靶向治疗药物治疗中出现在几种癌症类型中。该项目旨在完全剖析这一途径，并发现其他这样的途径途径，了解抵抗状态脆弱性的基础，并学习如何利用它们以安全有效的方式进行治疗。