Defining mechanisms of cancer chemoresistance and metastasis

定义癌症化疗耐药和转移的机制

• 批准号: 8425810
• 负责人: Swarnali Acharyya
• 金额: $ 15.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425810
• 关键词: 4q21; Address; Adenocarcinoma; Advanced Malignant Neoplasm; Affect; Animal Model; Applications Grants; Area; Award; Biological; Biological Assay; Biology; Blood; Breast Cancer Cell; Breast Cancer Model; CXCL1 gene; Calculi; Cancer Patient; Cell Survival; Cells; Cellular biology; Chemoprotective Agent; Clinic; Clinical; Clinical Management; Communities; Complement; Critiques; Cytotoxic Chemotherapy; Data; Disease; Drug resistance; Endothelial Cells; Environment; Failure; Fibroblasts; Gene Components; Genotoxic Stress; Goals; Hospitals; Human; ITGAM gene; Immune; Individual; Inflammatory; Invaded; Investigation; Kinetics; Knowledge; Laboratories; Lead; Light; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic Lesion; Mining; Mission; Modeling; Morbidity - disease rate; Myeloid Cells; Neoadjuvant Therapy; Neoplasm Metastasis; Organ; Paracrine Communication; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Quality of life; Research; Research Institute; Research Personnel; Residual state; Resistance; Resources; Role; S100A8 gene; Sampling; Site; Smooth Muscle Myocytes; Source; Stress; Structure of parenchyma of lung; TNF gene; Testing; Therapeutic; Time; Tissues; Training; Tumor Necrosis Factor-alpha; Universities; Work; Writing; anticancer research; base; bone; cancer cell; cancer type; career; cell type; chemokine; chemotherapy; clinically relevant; cytokine; design; drug development; human TNF protein; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; malignant breast neoplasm; medical schools; meetings; mortality; neoplastic cell; novel; overexpression; paracrine; post-doctoral training; preclinical study; prevent; programs; resistance mechanism; response; small molecule; standard of care; therapy resistant; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): My long-term career goal is to contribute to cancer research as an independent investigator that will lead to better ways of treating cancer. It is wel known that 90% of cancer patients die because of metastasis, which results in the spreading of tumor cells to different organs such as lung and bone. As an important step towards achieving my career goal, I joined the laboratory of Dr. Joan Massague, one of the leaders in breast cancer metastasis field for my postdoctoral training. Located in the world's premier cancer research institutes, Memorial Sloan Kettering Cancer Center, this research environment provides unparalleled resources and expertise from clinicians and basic researchers. Innovative research at MSKCC is encouraged and is complemented with inputs from the tri-institutional community comprising of Rockefeller University, Weill-Cornell Medical College and clinical input from investigators from the Memorial Hospital. My work in Dr. Massague's laboratory sheds light on how the tumor microenvironment responds to chemotherapy to benefit cancer cell survival. Our evidence from animal models and clinical samples suggest that chemotherapy induces a burst of cytokines including TNF-¿ from several components of the tumor microenvironment such as endothelial and smooth muscle cells. An undesirable consequence of the stromal TNF-¿ is to boost CXCL1/2 expression in breast cancer cells. A higher level of CXCL1/2 then drives the paracrine loop involving myeloid cell-derived S100A8/9 to enhance cancer cell survival. An adverse cycle involving TNF-¿-CXCL1/2- S100A8/9 could thus be expanded in response to chemotherapy. Once initiated, this chemoprotective program could become self-sustaining, leading to the enrichment of residual aggressive clones able to resist chemotherapy and thrive in the lung parenchyma and elsewhere. Obtaining a transitional award would be an ideal stepping-stone to independence with a mentored and independent phase. Based on our previous findings, my research plan critically addresses the role of the TNF-¿-CXCL1/2-S100A8/9 axis in chemoresistance and metastasis in two different cancer types, breast and lung cancer. In the case of breast cancer proposed for the K99 phase, based on our work I will interrogate the link between chemotherapy, kinetics and biology of myeloid cell recruitment and metastasis progression in breast cancer models. The second aim will focus on devising ways of targeting the TNF-alpha-CXCL1/2-S100A8/9 axis most effectively. During this time, I will gain training in the area of lung cancer and familiarize myself with lung cancer metastasis models. In my independent phase, I will continue to focus on the components of the TNF-alphaCXCL1/2-S100A8/9 axis (GOIs) that are activated with chemotherapy or during metastasis. In Aim 4, I will dissect the functional contribution of the GOIs in mediating chemoresistance linked metastasis.

描述（由适用提供）：我的长期职业目标是作为独立研究者为癌症研究做出贡献，这将导致更好的治疗癌症方法。众所周知，有90％的癌症患者因转移而死亡，这导致肿瘤细胞扩散到肺和骨骼等不同器官。作为实现职业目标的重要一步，我加入了琼·马萨格（Joan Massague）博士的实验室，琼·马萨格（Joan Massague）博士是乳腺癌转移领域的领导者之一，接受了博士后培训。该研究环境位于纪念斯隆·凯特林癌症中心的世界首屈一指的癌症研究机构，提供了临床医生和基础研究人员的无与伦比的资源和专业知识。鼓励MSKCC的创新研究，并完成了洛克菲勒大学，Weill-Cornell医学院的三机构社区完成的投入，以及纪念医院的调查人员的临床投入。 我在Massague博士的实验室中的工作阐明了肿瘤微环境对化学疗法的反应如何使癌细胞存活率受益。我们来自动物模型和临床样品的证据表明，化学疗法诱导了一系列细胞因子，包括来自肿瘤微环境的几个成分（例如内皮和平滑肌细胞）的细胞因子。基质TNF-€的不良后果是增强乳腺癌细胞中的CXCL1/2表达。然后，较高水平的CXCL1/2驱动涉及髓样细胞衍生的S100A8/9的旁分泌环，以增强癌细胞的存活。因此，涉及TNF-¿-CXCL1/2- S100A8/9的不利循环可以响应化学疗法而扩展。一旦开始，该化学保护程序就会变得自我维持，从而富集了能够抵抗化学疗法并在肺实质和其他地方壮成长的残留攻击性克隆。获得过渡性奖励将是通过指导和独立阶段独立的理想垫脚石。根据我们以前的发现，我的研究计划批判性地解决了TNF-�-CXCL1/2-S100A8/9轴在两种不同的癌症类型的化学耐药性和转移中的作用，乳腺癌和肺癌。在乳腺癌的情况下，根据我们的工作，我将询问乳腺癌模型中髓样细胞募集的化学疗法，动力学和生物学之间的联系。第二个目标将重点放在靶向靶向TNF-Alpha-CXCL1/2-S100A8/9轴的方法上。在此期间，我将在肺癌领域接受培训，并熟悉肺癌转移模型。在我的独立阶段，我将继续关注TNF-AlphACXCL1/2-S100A8/9轴（GOIS）的组件，这些组件被化学疗法或转移过程中激活。在AIM 4中，我将在介导化学耐药性转移时剖析Gois的功能贡献。