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：
9134619
负责人：
David R Soto Pantoja
金额：
$ 15.96万
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134619
关键词：
4T1 Ablation Accounting 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 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 Health 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 killings 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 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NCI-Cancer培训奖的David R. Soto Pantoja博士的K22职业发展奖的重新提交申请。 Pantoja博士在分子生物学和癌症生物学领域具有广泛的专业知识。他已经成功地通过国防部的培训部培训奖获得了对他的研究的竞争支持，并且是获得NCI董事职业发展创新奖的博士后研究员。他召集了一个多学科委员会，并将参加课程工作，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。这笔赠款对于完成Pantoja博士的职业目标至关重要。该提案的目的是找到减少肿瘤生长，克服对化疗的抵抗力发展并减少乳腺癌转移的新机制，乳腺癌每年造成40,000多人死亡。发表的证据表明，CD47的阻滞增强了肿瘤的局部辐射生长延迟，同时保护正常组织。 Pantoja博士的主要出版物表明，CD47封锁的放射保护机制是通过激活保护性自噬来进行的。该应用提出，通过选择性激活线粒体增加线粒体周转率，该机制被激活以使癌细胞对治疗敏感。癌细胞在某种程度上对线粒体积累产生了抵抗力，从而导致刺激促生存途径的活性氧增加。当前克服这个问题的机制知之甚少。因此，在此应用中提出，通过主要通过减少活性葡萄糖代谢和增加线粒体激活来调节生物能量来阻断CD47通过调节生物能量来封锁乳腺癌细胞。该提议通过用于调查假设，国家癌症研究所内的大量资源以及匹兹堡大学和匹兹堡大学和乔治敦大学的合作者的互补和丰富工具进行了加强，并捕捉了Pantoja博士在乳腺癌耐药性，细胞生物学，自动噬菌体和CD47的顾问的开拓性工作。这些领域的结合以及这些研究的完成将验证用于治疗侵入性乳腺癌以及其他主要癌症的新型治疗靶标。