Mechanisms of extracellular matrix mediated drug resistance

细胞外基质介导的耐药机制

• 批准号: 8566599
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566599
• 关键词: Address; Adhesions; Adverse effects; Advisory Committees; Award; Cancer Patient; Cells; Clinic; Combined Modality Therapy; Critiques; Cues; Dana-Farber Cancer Institute; Data; Development; Disease; Disease remission; Drug Combinations; Drug resistance; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Foundations; Future; Goals; Hospitals; In Vitro; Individual; 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; Writing; 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; meetings; neoplastic cell; novel; public health relevance; 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）：本提案旨在阐明导致乳腺癌中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（>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开发针对这一途径。不幸的是，临床结果有些令人失望，表明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，可以规避抑制剂的作用，导致耐药性。因此，我们将重点放在鉴定对PI3K/mTOR抑制剂的耐药机制上。针对这种耐药性的有效药物组合策略的开发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的线索，使它们能够在治疗中存活下来