New therapeutic vulnerabilities in breast cancer

项目总结/摘要 本提案介绍了由三个研究小组组成的联合体在以下方面的现有活动和拟议的未来活动： 马萨诸塞州波士顿地区，其研究在过去二十年中一直集中在 人类乳腺癌所有三位现任项目负责人和病理学核心都曾在以前的 P01由Robert温伯格博士（Whitehead Institute for Biomedical Research，剑桥，MA）领导了21年。 因此，拟议的小组有着长期的富有成效的合作项目历史， 建立促进互动的机制。三个研究小组的主要重点是改善我们的 了解对目前使用的疗法的耐药机制，并确定和表征新的 治疗目标和联合治疗，目标是将该计划的临床前 事实上，我们的一些发现已经启发了FDA批准的治疗方法的设计， 几项临床试验正在进行中各组成小组的领导人和受训者之间的互动 是通过召开整个学年的每月研究会议和一个单一的研究务虚会驱动的 在马萨诸塞州西部，在此期间，参与实验室的受训人员会面并介绍详细信息 各自的研究成果。这个联合体的生产力取决于互补研究 各组成小组的兴趣和实验方法。参与小组讨论了治疗性 乳腺癌的耐药性和新的脆弱性从不同的角度来看，从定义开始， 细胞对生长调节信号反应的异质性的分子机制， 剖析治疗抗性中的表观遗传和转录组异质性， 远处转移各参与项目小组的研究重点分别为： 互补和融合。这种互补性表现在两个区域反复的异花受精。 概念层面，一个项目与其他项目共享试剂，互补技术， 成功的联合出版物。

Project Summary/Abstract This Proposal describes the existing and proposed future activities of a consortium of three research groups in the Boston, MA area whose research has been focused over the past two decades on the pathogenesis of human breast cancer. All three current Project Leaders and the Pathology Core have worked together in a prior P01 led by Dr. Robert Weinberg (Whitehead Institute for Biomedical Research, Cambridge, MA) for 21 years. As such, the proposed Team has a long history of productive collaborative projects and well-established mechanisms in place to facilitate interactions. The primary focus of the three research groups is to improve our understanding of mechanisms of resistance to currently used therapies and to identify and characterize new therapeutic targets and combination therapies with the goal of clinical translation of the Program's preclinical findings; indeed, some of our findings have already inspired the design of FDA-approved therapeutics with several clinical trials in progress. The interactions between the Leaders and trainees of the component Groups is driven by convening monthly research meetings throughout the academic year and a single research retreat in Western Massachusetts, during which trainees in the participating laboratories meet and present the details of their respective research findings. The productivity of this consortium depends on the complementary research interests and experimental approaches of the component Groups. The participating Groups address therapeutic resistance and novel vulnerabilities in breast cancer from various perspectives, beginning with the defining molecular mechanisms underlying heterogeneity in cellular responses to growth regulatory signals and dissecting epigenetic and transcriptomic heterogeneity in therapeutic resistance and in driving the outgrowth of distant metastases. The respective research emphases of the participating Project Groups are highly complementary and integrated. This complementarity is manifested through repeated cross-fertilization at the conceptual level, the sharing of reagents generated by one Project with others, complementary technologies, and successful joint publications.