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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.

抽象的靶向治疗和免疫治疗是两个最具变革性和最有前途的进展过去二十年的癌症治疗。然而，与传统化疗一样，它们经常屈服于癌症最终抵抗对其脆弱性的治疗攻击的能力，扭转了最初的状态这些治疗的临床反应令人印象深刻。该项目重点关注保守的非突变多种治疗中出现的耐药性中经常遇到的耐药机制跨多种癌症类型的治疗方案。在 CTD2 网络的当前阶段，我们开发了强大的新功能使社区能够识别新的癌症脆弱性的工具和功能。该方法依赖于癌症治疗响应门户 (CTRP)，其中包含大量定量化合物数据集敏感性数据并已不受限制地提供。使用 CTRP，我们找到了证据至少存在一种常见的治疗抵抗状态，与间充质特征相关癌细胞。重要的是，这种状态是通过化疗或靶向治疗产生的跨越多种癌症类型。该项目旨在充分剖析这条途径，并发现其他类似的途径路径，了解抵抗状态漏洞的基础，并学习如何利用它们以安全有效的方式进行治疗。