Mechanisms of extracellular matrix mediated drug resistance

细胞外基质介导的耐药机制

• 批准号: 9349842
• 负责人: Taru Eliisa Muranen
• 金额: $ 24.9万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-02 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349842
• 关键词: Address; Adhesions; Adverse effects; Advisory Committees; Award; Breast Cancer Patient; Cells; Clinic; Combined Modality Therapy; Cues; Dana-Farber Cancer Institute; Data; Development; Disease; Disease remission; Drug Combinations; Drug resistance; Environment; Extracellular Matrix; Extracellular Matrix Proteins; FRAP1 gene; Foundations; Future; Goals; Health; Hospitals; In Vitro; Integrin Binding; Integrins; Investigation; Knowledge; Lead; Learning; Link; Malignant Neoplasms; Mediating; Mentors; Messenger RNA; Modeling; Molecular; Mutation; Normal tissue morphology; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Process; Protein Array; Protein Biosynthesis; Regulation; Relapse; Research Personnel; Resistance; Role; Signal Transduction; Solid Neoplasm; Stable Disease; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Training Activity; Translating; Translations; Tumor Biology; Up-Regulation; Work; Xenograft Model; base; cancer cell; cancer therapy; career; combinatorial; design; in vivo; inhibitor/antagonist; innovation; killings; mTOR Inhibitor; mTOR inhibition; malignant breast neoplasm; medical schools; neoplastic cell; novel; research study; resistance mechanism; response; skills; success; targeted treatment; tool; transcription factor; tumor; tumor microenvironment

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.

描述(申请人提供)：本提案旨在阐明导致乳腺癌对PI3K/mTOR抑制剂耐药的潜在分子机制。PI3K/mTOR通路是乳腺癌中最常见的激活通路之一(&gt；70%)，为治疗干预提供了一个有吸引力的靶点。已经有越来越多的抑制剂被开发出来针对这一途径。不幸的是，来自临床的结果有些令人失望，显示这些抑制剂作为单一药物的效果很小。这可能是由于代偿途径的激活，可以绕过抑制剂的影响，导致耐药性。因此，我们致力于PI3K/mTOR抑制剂耐药机制的研究。针对这种耐药性开发有效的药物组合策略将使大量乳腺癌患者受益。我们之前的研究表明，与细胞外基质的接触为癌细胞提供了关键信号，使它们能够在治疗中存活下来。 使用PI3K/mTOR抑制剂，而不接触基质的细胞仍然敏感。这种基质依赖的耐药性是由于药物治疗在癌细胞中引发的适应性反应。这种适应性反应包括几条生存途径的上调，部分是由FOXO转录因子和蛋白质合成调节的。这项工作确定了蛋白质合成调节在介导耐药中的关键作用，在本提案中，我们计划扩大这一重要的、尽管很少被探索的对PI3K/mTOR抑制剂耐药机制的方面。这些观察结果将构成这项提议的基础。阐明基质介导耐药的确切分子机制将为合理开发有效的联合治疗方法提供基础。这项建议概述了体外和体内的研究路线，以确定基质介导的耐药性的基础。在这项建议中，我将：1)确定直接与基质黏附有关的分子和机制，这些分子和机制有助于启动适应性反应；2)研究基质黏附如何调节蛋白质合成以及如何导致耐药性；3)通过比较肿瘤和正常组织中药物诱导的适应性反应来识别肿瘤特异性分子；以及4)利用这些数据设计和测试新型肿瘤特异性联合疗法，以克服基质介导的耐药性，同时将正常组织中的不良反应降至最低。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。导师阶段将让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，我组建了一个由我提议学习的领域的主要专家组成的咨询委员会。这个顾问委员会包括我的导师Joan Brugge博士(哈佛医学院)、John Blenis博士(哈佛医学院)、Kornelia Polyak博士(Dana Farber癌症研究所)和David Sabatini博士(Whitehead/MIT)。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，并成功启动我作为独立调查人员的职业生涯。