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Defining mechanisms of cancer chemoresistance and metastasis

定义癌症化疗耐药和转移的机制

基本信息

批准号：
9064096
负责人：
Swarnali Acharyya
金额：
$ 24.65万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064096
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 Breast Cancer Patient Breast cancer metastasis CXCL1 gene Cancer Patient Cell Survival Cells Cellular biology Clinic Clinical Clinical Management Communities Complement Cytotoxic Chemotherapy Data Disease Drug resistance Endothelial Cells Environment Failure Fibroblasts Gene Components Genotoxic Stress Goals Hospitals Human ITGAM gene Immune Inflammatory Invaded Investigation Kinetics Knowledge Laboratories Lead Light Link Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Memorial Sloan-Kettering Cancer Center Mentors 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 Universities Work abstracting anticancer research base bone cancer cell cancer subtypes cancer type career cell type chemokine chemotherapy clinically relevant cytokine design drug development improved in vivo innovation insight interest malignant breast neoplasm medical schools mortality neoplastic cell novel overexpression paracrine post-doctoral training preclinical trial prevent programs resistance mechanism response small molecule inhibitor standard of care therapy resistant tumor tumor microenvironment

项目摘要

Abstract: 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 well 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 chemo- protective 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-�-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-�-CXCL1/2-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.

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