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Project 2: Nitric Oxide in the Tumor Micorenviroment of Triple Negative Breast Cancer

项目2：三阴性乳腺癌肿瘤微环境中的一氧化氮

基本信息

批准号：
10246956
负责人：
WILLIAM R. MONTFORT
金额：
$ 14.98万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246956
关键词：
4T1 Address Affect Aggressive behavior Allografting Arizona Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Cancer therapy Budgets CD47 gene CRISPR/Cas technology Cancer Biology Cancer Center Cells Clinical Research Collaborations Communities Cytotoxic T-Lymphocytes Data Disseminated Malignant Neoplasm Education and Outreach Ensure Epidermal Growth Factor Receptor Ethnic Origin Focus Groups Funding Gene Expression Profile Genes Glycolysis Goals Grant Growth HIF1A gene Human Hypoxia Hypoxia Inducible Factor Immune Immune Evasion Immune system Immunocompetent Immunohistochemistry Immunosuppression In Vitro Investigation Laboratories Link MCF10A cells MCF7 cell MDA-MB-468 Malignant Neoplasms Membrane Proteins Metastatic breast cancer Modeling Monitor Mus Myeloid-derived suppressor cells NOS2A gene Native Americans Natural Immunity Natural Killer Cells Navajo Nitric Oxide Nitric Oxide Signaling Pathway Nonmetastatic Not Hispanic or Latino Oncology Outcome PIM1 gene Paper Patients Phenotype Phosphotransferases Population Procollagen-Proline Dioxygenase Production Proteins Publications Research Research Personnel Role Scientist Signal Transduction Solid Soluble Guanylate Cyclase Students Therapeutic Training Translational Research Tumor Cell Invasion Tumor Escape Tumor Promotion Tumor Suppressor Proteins Tumor-Derived Universities Vascularization Woman Work Xenograft procedure adaptive immune response anticancer research base cancer prevention career cell motility chemokine cytokine education research experimental study high risk immune checkpoint blockade immune clearance in vivo in vivo Model inhibitor/antagonist macrophage malignant breast neoplasm migration mouse model neoplastic cell novel therapeutic intervention novel therapeutics professor programmed cell death ligand 1 receptor recruit side effect structural biology student training targeted treatment therapeutic development transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT: PROJECT 2 NITRIC OXIDE IN THE TUMOR MICROENVIRONMENT OF TRIPLE NEGATIVE BREAST CANCER We propose to uncover how tumor produced nitric oxide drives tumor aggressiveness and immune evasion in triple negative breast cancer (TNBC). We also seek to increase research opportunities in cancer biology for Native American students. TNBC is an aggressive and metastatic form of breast cancer for which there are no targeted therapies. TNBC disproportionately affects Native American women and leads to worse outcomes than for non-Hispanic White women. Overall, Native American women have a 30-70% higher risk of dying from breast cancer when compared to other ethnicities. Our long-term goals are to develop much-needed new therapies for TNBC and to increase the pool of Native Americans with a focus on cancer research. Our team brings together Dr. Narendiran Rajasekaran, an Assistant Professor at Northern Arizona University (NAU) with a strong background in cancer biology and innate immunity, and Dr. William Montfort, a University of Arizona Cancer Center Professor with strength in structural biology, therapeutic development and nitric oxide signaling. Our project meshes with the Partnership for Native American Cancer Prevention (NACP) through our focus on a form of cancer of high importance to the Native American community, and through our efforts to train emerging Native American scientists in cancer biology. Our preliminary data uncover a link between tumor-derived nitric oxide and enhanced hypoxic signaling, which leads to a gene expression profile favoring tumor promotion, including growth, glycolysis, migration and immune cell evasion. We have three aims. Aim 1 is to uncover how nitric oxide induces tumor progression, using three breast cancer cell lines for in vitro work and the 4T1 allograft murine model for in vivo work. Aim 2 is to uncover how nitric oxide induces tumor evasion of innate immunity through checkpoint blockade involving CD47 and PD-L1, and cytokine production. Focus is on both macrophages and natural killer cells and will make use of both xenograft and allograft breast cancer models. Aim 3 is to recruit and train Native American students in cancer biology and increase the opportunities for cancer research at NAU. Native American students will be recruited into both laboratories. A particular focus will be on ensuring Prof. Rajasekaran successfully establishes his new laboratory at NAU with solid student training, funding and publications.

项目总结/摘要：项目2 三阴性乳腺癌肿瘤微环境中的一氧化氮我们建议揭示肿瘤产生的一氧化氮如何驱动肿瘤的侵袭性和免疫逃避，三阴性乳腺癌（TNBC）。我们还寻求增加癌症生物学的研究机会，美国本土学生。TNBC是一种侵袭性和转移性的乳腺癌，靶向治疗。TNBC不成比例地影响美洲原住民妇女，并导致比为非西班牙裔白色女性。总的来说，美洲原住民妇女死于乳腺癌的风险高出30-70%，与其他种族相比，我们的长期目标是开发急需的新疗法， TNBC和增加美洲原住民的游泳池，重点是癌症研究。我们的团队汇集了博士Narendiran Rajasekaran是北方亚利桑那大学（NAU）的助理教授，具有癌症生物学和先天免疫学背景，亚利桑那州癌症大学的William Montfort博士中心教授，在结构生物学，治疗开发和一氧化氮信号传导方面具有优势。我们通过我们对表格的关注，该项目与美洲原住民癌症预防合作伙伴关系（NACP）相结合癌症的高度重要性，以美洲原住民社区，并通过我们的努力，培养新兴的土著美国癌症生物学科学家。我们的初步数据揭示了肿瘤源性一氧化氮和增强的缺氧信号之间的联系，导致有利于肿瘤促进的基因表达谱，包括生长、糖酵解、迁移和免疫细胞逃避我们有三个目标。目的1是揭示一氧化氮如何诱导肿瘤进展，使用三种乳腺癌细胞，癌细胞系用于体外工作，4 T1同种异体移植鼠模型用于体内工作。目标2是揭示如何一氧化氮通过涉及CD 47和PD-L1的检查点阻断诱导先天免疫的肿瘤逃避，和细胞因子的产生。重点是巨噬细胞和自然杀伤细胞，并将利用两者异种移植和同种异体移植乳腺癌模型。目标3是招募和培训美洲原住民癌症学生生物学和增加在NAU癌症研究的机会。美国原住民学生将被招募两个实验室。一个特别的重点将是确保Rajasekaran教授成功地建立他的新的 NAU实验室与坚实的学生培训，资金和出版物。