Mechanisms of extracellular matrix mediated drug resistance

细胞外基质介导的耐药机制

• 批准号: 8712425
• 负责人: Taru Eliisa Muranen
• 金额: $ 10.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712425
• 关键词: Address; Adhesions; Adverse effects; Advisory Committees; Award; 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; 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; 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; human FRAP1 protein; 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; 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（由申请人提供）：该提案旨在阐明导致乳腺癌对 PI3K/mTOR 抑制剂产生耐药性的潜在分子机制。 PI3K/mTOR 通路是乳腺癌中最常激活的通路之一 (>70%)，并为治疗干预提供了有吸引力的靶点。针对该途径开发了越来越多的抑制剂。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甚微。这可能是由于补偿途径的激活可以规避抑制剂的作用，从而导致耐药性。因此，我们的重点是鉴定 PI3K/mTOR 抑制剂的耐药机制。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线索，使它们能够在治疗中存活下来 使用 PI3K/mTOR 抑制剂，而没有基质接触的细胞仍然敏感。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所致。这种适应性反应包括多种生存途径的上调，部分是由 FOXO 转录因子和蛋白质合成的调节来协调的。这项工作确定了蛋白质合成调节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 PI3K/mTOR 抑制剂耐药机制的这一重要方面（尽管很少探索）。这些意见将构成本提案的基础。阐明基质介导的耐药性背后的确切分子机制将为开发有效组合疗法的合理方法提供基础。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。在这个提案中，我将：1）识别与基质粘附直接相关的分子和机制，有助于启动适应性反应，2）研究基质粘附如何调节蛋白质合成以及这如何导致耐药性，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，4）利用这些数据来设计和测试 新型肿瘤特异性联合疗法可克服基质介导的耐药性，同时最大限度地减少对正常组织的不良影响。这些研究的成功与拟议的培训活动直接相关 我打算在该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，重点关注乳腺癌，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向职业生涯独立阶段的过渡，我组建了一个由我建议学习领域的顶尖专家组成的咨询委员会。该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（达纳法伯癌症研究所）和 David Sabatini 博士（Whitehead/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，以及成功开展我作为独立研究者的职业生涯。