Therapeutic targeting of CD47 regulates tumor cell bioenergetics and mitophagy

CD47 的治疗靶向调节肿瘤细胞生物能和线粒体自噬

基本信息

批准号：
9775601
负责人：
David R Soto Pantoja
金额：
$ 7.16万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9775601
关键词：
4T1 Ablation Adhesions Animals Anthracyclines Area Autophagocytosis Award BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like Bioenergetics Bioinformatics Breast Cancer Cell Breast Cancer Model Breast Carcinogenesis Breast Carcinoma Breast cancer metastasis CD47 gene Cancer Biology Cancer Cell Growth Cancer Etiology Cause of Death Cell Proliferation Cell Survival Cells Cellular Metabolic Process Cellular biology Cessation of life Complement Cytotoxic Chemotherapy Data Department of Defense Diagnosis Disease Disease Progression Doxorubicin Drug resistance Energy Metabolism Ensure Event Funding Mechanisms Genus Hippocampus Glucose Goals Grant Growth Histologic Human In Vitro Ionizing radiation K-Series Research Career Programs Lead MDA MB 231 Malignant Neoplasms Mammary Neoplasms Measures Mediating Metabolic Mitochondria Modality Modeling Molecular Molecular Biology Morbidity - disease rate Mus National Cancer Institute Neoplasm Metastasis Normal tissue morphology PINK1 gene Pathway interactions Patients Pilot Projects Postdoctoral Fellow Principal Investigator Process Publications Publishing Radiation Radioprotection Reactive Oxygen Species Regulation Research Support Resistance Resistance development Resources Role SLC2A1 gene Scheme Signal Transduction System Testing Training Training Programs Tumor Burden United States United States National Institutes of Health Universities Woman Work blood glucose regulation cancer cell cancer imaging cancer therapy career career development chemotherapy dimethylbenzanthracene glucose metabolism glucose transport in vivo Model innovation insight malignant breast neoplasm metabolic profile migration mitochondrial metabolism mortality mouse model multidisciplinary neoplastic cell new therapeutic target novel novel strategies novel therapeutics parkin gene/protein pre-doctoral programs public health relevance receptor skills targeted agent targeted treatment therapeutic target tool tumor tumor growth tumor microenvironment tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): This is a resubmission application for a K22 Career development award for Dr. David R. Soto Pantoja, an NCI-Cancer Training Award Fellow at, National Institutes of Health. Dr. Pantoja has extensive expertise in the areas of molecular biology and cancer biology. He has been successful in obtaining competitive support for his research through a Department of Defense predoctoral training award and as a postdoctoral fellow obtaining a NCI Directors Career Development Innovation Award. He has assembled a multidisciplinary committee and will participate in course work to complement his expertise in cancer biology to ensure the successful transition into an independent career. This grant will be essential for the completion of Dr. Pantoja's career goals. The objectives of this proposal are to find novel mechanisms to reduce tumor growth, overcome development of resistance to chemotherapy and reduce metastasis of breast cancer, which is responsible for over 40,000 deaths every year in the United States. Published evidence shows that blockade of CD47 enhances local radiation growth delay of tumors while protecting normal tissue. Dr. Pantoja's key publications show of that the mechanism of radioprotection with CD47 blockade is through activation of protective autophagy. This application proposes that this mechanism is activated to sensitize cancer cells to therapy by the selective activation of mitophagy increasing mitochondrial turnover. Cancer cells develop resistance to chemotherapy in part to accumulation of mitochondria leading to increase in reactive oxygen species that stimulate pro-survival pathways. The current mechanism to overcome this issue is poorly understood. Therefore it is proposed in this application that blockade of CD47 sensitizes breast cancer cells by regulating bioenergetics mainly by reducing the active glucose metabolism and through increased activation of mitophagy. This proposal is strengthened by the complementary and rich tool set used to investigate the hypothesis, the vast resources available within the National Cancer Institute and collaborators at the University of Pittsburgh and Georgetown University and captures the pioneering work of Dr. Pantoja's advisors in the areas of breast cancer resistance, cell bioenergetics, autophagy and the CD47 signaling axis. The combination of these fields and the completion of these studies will validate novel therapeutic targets for treating invasive breast cancer as well as other major cancers.

描述（由申请人提供）：这是美国国立卫生研究院 NCI 癌症培训奖研究员 David R. Soto Pantoja 博士重新提交的 K22 职业发展奖申请。 Pantoja 博士在分子生物学和癌症生物学领域拥有丰富的专业知识。他通过国防部博士前培训奖成功为其研究获得了竞争性支持，并作为博士后研究员获得了国家癌症研究所董事职业发展创新奖。他组建了一个多学科委员会，并将参与课程工作，以补充他在癌症生物学方面的专业知识，以确保成功过渡到独立职业。这笔赠款对于潘托哈博士完成职业目标至关重要。该提案的目标是寻找新的机制来减少肿瘤生长、克服化疗耐药性并减少乳腺癌转移，乳腺癌每年导致美国超过 40,000 人死亡。已发表的证据表明，阻断 CD47 可增强肿瘤的局部放射生长延迟，同时保护正常组织。 Pantoja 博士的主要出版物表明，CD47 阻断的放射防护机制是通过激活保护性自噬。该申请提出，通过选择性激活线粒体自噬增加线粒体周转，激活该机制以使癌细胞对治疗敏感。癌细胞对化疗产生耐药性，部分原因是线粒体的积累导致活性氧的增加，从而刺激促生存途径。目前克服这一问题的机制尚不清楚。因此，在本申请中提出，CD47的阻断主要通过减少活跃的葡萄糖代谢和通过增加线粒体自噬的激活来调节生物能而使乳腺癌细胞敏化。用于研究该假设的补充和丰富的工具集、国家癌症研究所以及匹兹堡大学和乔治城大学的合作者提供的大量资源加强了该提案，并体现了 Pantoja 博士的顾问在以下领域的开创性工作：乳腺癌抵抗、细胞生物能学、自噬和 CD47 信号轴。这些领域的结合以及这些研究的完成将验证治疗浸润性乳腺癌以及其他主要癌症的新治疗靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer.

DOI：
10.1038/oncsis.2016.37
发表时间：
2016-05-30
期刊：
Oncogenesis
影响因子：
6.2
作者：
Soto-Pantoja DR;Sipes JM;Martin-Manso G;Westwood B;Morris NL;Ghosh A;Emenaker NJ;Roberts DD
通讯作者：
Roberts DD