Mechanisms of extracellular matrix mediated drug resistance

描述（由申请人提供）：该提案旨在阐明导致乳腺癌对PI 3 K/mTOR抑制剂耐药的潜在分子机制。PI 3 K/mTOR通路是乳腺癌中最常见的激活通路之一（>70%），并且为治疗干预提供了有吸引力的靶标。已经开发了越来越多的抑制剂来靶向该途径。不幸的是，临床结果有些令人失望，显示这些抑制剂作为单一药物的疗效很小。这可能是由于代偿途径的激活，可以绕过抑制剂的作用，导致耐药性。因此，我们将我们的努力集中在鉴定对PI 3 K/mTOR抑制剂的抗性机制上。开发针对这种耐药性的有效药物组合策略将使大量乳腺癌患者受益。我们以前的研究表明，与细胞外基质的接触为癌细胞提供了关键的线索，使它们能够在治疗中存活下来 与PI 3 K/mTOR抑制剂，而没有基质接触的细胞保持敏感。这种基质依赖性耐药性是由于药物治疗在癌细胞中引起的适应性反应。这种适应性反应包括上调几种生存途径，并部分由FOXO转录因子和蛋白质合成的调节来协调。这项工作确定了调节蛋白质合成在介导耐药性中的关键作用，并且在本提案中，我们计划扩展PI 3 K/mTOR抑制剂耐药机制的这一重要方面，尽管很少探索。这些意见将构成本建议的基础。阐明基质介导的耐药的确切分子机制将为开发有效的组合疗法提供合理的方法。该提案概述了体外和体内研究路线，以确定基质介导的耐药性的基础。在本提案中，我将：1）鉴定与有助于启动适应性反应的基质粘附直接相关的分子和机制，2）研究基质粘附如何调节蛋白质合成以及这如何有助于耐药性，3）通过比较肿瘤和正常组织中药物诱导的适应性反应来鉴定肿瘤特异性分子，和4）利用这些数据来设计和测试新的肿瘤特异性组合治疗剂，以克服基质介导的药物抗性，同时使正常组织中的副作用最小化。这些研究的成功与拟议的培训活动直接相关 我打算在这个奖项的指导阶段进行。指导阶段将使我加深对肿瘤生物学的理解，专注于乳腺癌，并在哈佛医学院及其附属医院的高度支持和创新的培训环境中获得高级培训。此外，为了支持我的培训，以及在我向职业生涯的独立阶段过渡的过程中，我组建了一个咨询委员会，由我建议学习的领域的顶尖专家组成。这个咨询委员会包括我的导师琼·布鲁格博士（哈佛医学院）、约翰·布莱尼斯博士（哈佛医学院）、科妮莉亚·波利亚克博士（达纳·法伯癌症研究所）和大卫·萨巴蒂尼博士（怀特黑德/麻省理工学院）。在该奖项的指导阶段获得的技能和知识将有助于上述拟议的研究和未来的研究，并成功地启动我的职业生涯作为一个独立的调查员。

DESCRIPTION (provided by applicant): This proposal aims at elucidating the underlying molecular mechanisms that lead to drug resistance to PI3K/mTOR inhibitors in breast cancer. The PI3K/mTOR pathway is one of the most commonly activated pathways in breast cancer (>70%), and provides an attractive target for therapeutic intervention. There has been an increasing number of inhibitors developed to target this pathway. Unfortunately, the results from the clinic have been somewhat disappointing, showing only little efficacy for these inhibitors acting as single agents. This is likely due to activation of compensatory pathways that can circumvent the effect of the inhibitors, leading to drug resistance. Therefore, we have focused our efforts on the identification of mechanisms of resistance to PI3K/mTOR inhibitors. The development of efficient drug combination strategies targeting this resistance would benefit a large number of breast cancer patients. Our previous studies showed that contact with the extracellular matrix provides cancer cells with critical cues that permit them to survive treatment with PI3K/mTOR inhibitors, whereas, cells without matrix contact remained sensitive. This matrix-dependent drug resistance was due to adaptive responses that the drug treatment elicited in cancer cells. This adaptive response included up-regulation of several survival pathways and was orchestrated in part by FOXO transcription factors and by regulation of protein synthesis. This work identified a critical role for the regulation of protein synthesis in mediating drug resistance, and, here in this proposal, we plan to expand this important, albeit little explored, aspect of the resistance mechanism to PI3K/mTOR inhibitors. These observations will form the foundation of this proposal. The elucidation of the exact molecular mechanism underlying the matrix-mediated drug resistance will provide the basis for a rational approach to the development of effective combinatorial therapies. This proposal outlines in vitro and in vivo lines of investigation to identify the basis of matrix-mediated drug resistance. In thi proposal I will: 1) identify molecules and mechanisms directly linked to the matrix-adhesions that contribute to the initiation of the adaptive response, 2) investigate how matrix-adhesion regulates protein synthesis and how this contributes to drug resistance, 3) identify tumor-specific molecules by comparing drug-induced adaptive responses in tumors and normal tissues, and 4) utilize these data to design and test novel tumor-specific combination therapeutics to overcome matrix-mediated drug resistance while minimizing adverse effects in normal tissues. The success of these studies is directly linked to the proposed training activities I intend to undertake during the mentored phase of this award. The mentored phase will allow me to deepen my understanding of tumor biology, concentrating on breast cancer, and to obtain advanced training in a highly supportive and innovative training environment of Harvard Medical School and the affiliated hospitals. In addition, to support me in my training, and in my transitio to the independent phase of my career, I have assembled an advisory committee of leading experts in the fields I propose studying. This advisory committee includes my mentor Dr. Joan Brugge (Harvard Medical School), Dr. John Blenis (Harvard Medical School), Dr. Kornelia Polyak (Dana Farber Cancer Institute) and Dr. David Sabatini (Whitehead/MIT). The skills and knowledge acquired during the mentored phase of this award will be instrumental for the above proposed studies and future studies, and for successfully launching my career as an independent investigator.