New therapeutic vulnerabilities in breast cancer

项目摘要/摘要 本提案描述了一个由三个研究小组组成的联合体在#年的现有活动和拟议的未来活动。 马萨诸塞州波士顿地区，过去20年来，该地区的研究重点是糖尿病的发病机制 人类乳腺癌。所有三位现任项目负责人和病理核心在之前的 P01由Robert Weinberg博士(位于马萨诸塞州剑桥的怀特黑德生物医学研究所)领导21年。 因此，拟议的团队在富有成效的合作项目方面有很长的历史，并建立了良好的 建立了促进互动的机制。三个研究小组的主要重点是改善我们的 了解当前使用的疗法的耐药机制，并识别和表征新的 以临床转化为目标的治疗目标和联合疗法 事实上，我们的一些发现已经启发了FDA批准的疗法的设计 几项临床试验正在进行中。成员组长与学员之间的互动 是通过在整个学年每月召开研究会议和一次研究务虚会来推动的 在马萨诸塞州西部，参与实验室的受训人员在此期间会面并介绍细节 他们各自的研究成果。该联盟的生产力取决于互补性研究 组成小组的兴趣和实验方法。参与小组的主题是治疗 从定义开始，从不同的角度看乳腺癌的耐药性和新的脆弱性 细胞对生长调节信号异质性反应的分子机制 剖析表观遗传和转录异质性在治疗耐药和在推动肿瘤生长中的作用 远处转移。参加项目小组各自的研究重点都很高 相辅相成、相互融合。这种互补性通过在水稻上反复杂交来体现。 概念层面，一个项目产生的试剂与其他项目共享，互补技术， 和成功的联合出版物。

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.