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Targeting of Doppel-axis to Control Lung Tumor Angiogenesis and Immunity

双轴靶向控制肺肿瘤血管生成和免疫

基本信息

批准号：
10522763
负责人：
Taslim A Al-Hilal
金额：
$ 34.89万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522763
关键词：
Adenocarcinoma Adult Affect Angiogenesis Inhibitors Animals Antibodies Attenuated Atypical adenomatous hyperplasia Awareness Binding Biology Blood Coagulation Disorders Blood Vessels Blood coagulation CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cancer Patient Carbon Dioxide Categories Cells Clinic Clinical Colorectal Data Deterioration Development Disease Dose Drug Kinetics Drug or chemical Tissue Distribution Drug usage Endothelial Cells Endothelial Growth Factors Receptor Ensure Genes Genetic Growth Health Human Hypertension Hypothyroidism Immune Immune checkpoint inhibitor Immunity Immunosuppression Immunotherapy Intestines KDR gene Kidney Knock-out Knockout Mice Life Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Molecular Target Molecular Weight Monoclonal Antibodies Monoclonal Antibody Therapy Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal tissue morphology Nutrient Oncogenes Oxygen Pathologic Pathway interactions Patients Perforation Perfusion Pharmaceutical Preparations Pharmacodynamics Phenotype Physiologic Neovascularization Physiological Play Process Proteins Proteinuria Receptor Protein-Tyrosine Kinases Regulatory T-Lymphocyte Reporting Resistance Role Safety Signal Transduction Signaling Molecule Speed Testing Testis Therapeutic Time Tissues Treatment Efficacy Tumor Angiogenesis Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factors Vascular blood supply angiogenesis bevacizumab blood vessel development cancer cell cancer therapy chemotherapeutic agent chemotherapy cytotoxic density experimental study gene function immune function improved inhibiting antibody male neutralizing monoclonal antibodies novel pharmacodynamic biomarker preclinical study prion-like response selective expression side effect thrombotic tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenic vascular bed wasting wound healing

项目摘要

Project summary Tumors, just like normal tissues, require blood vessels to receive nutrients and oxygen and to eliminate wastes and carbon dioxide. To ensure this blood supply, tumors create their own vascular beds from established blood vessels by a process called angiogenesis. This process plays a major role in tumor growth, survival, and invasiveness. Currently, various monoclonal antibodies (mAb) and small-molecular-weight drugs are used to restrain angiogenesis and starve tumors of nutrients. Bevacizumab and ramucirumab, for example, are two mAbs that inhibit angiogenesis-bevacizumab by binding with vascular endothelial growth factors (VEGF) and ramucirumab by blocking VEGF receptors (VEGFR). When used alone or in combination with chemotherapy, anti-angiogenic drugs slow down metastasis, stop disease deterioration, and extend the overall survival time of cancer patients. However, angiogenesis not only drives the growth of blood vessels in tumors, it also performs many important physiological functions in the body. The ‘good’ (physiological) angiogenesis regulates the thrombotic process, maintains vascular tone, and speeds up wound healing. Unfortunately, current anti-angiogenic drugs indiscriminately inhibit both good and ‘bad’ (tumor-directed) angiogenesis, thus resulting in blood-coagulation disorders, hypertension, hypothyroidism, proteinuria, and bowel perforation. In principle, it should be possible to reduce or eliminate many of the side effects of current anti-angiogenic drugs by blocking signaling molecules that are expressed only in tumor endothelial cells (TECs) but not in normal endothelial cells (NECs). Recently, we discovered that a prion-like protein called doppel is expressed only in TECs but not in NECs. In preliminary study, we showed that (i) doppel is expressed in both human and animal cancers; (ii) increased doppel expression in TECs (Dplhi-TECs) is associated with increased blood vessel density in tumors; (iii) doppel erasure from TECs and from mice (i.e., doppel knockout) reduces the number of vessels in tumors; (iv) anti-doppel mAb slows tumor growth in mice; and (v) doppel-knockout mice shows higher ratio of intratumoral CD8 versus regulatory T cells. Thus, we posit that Dplhi-TECs promote neoangiogenesis and create an immunosuppressive TME, and targeting of Dplhi-TECs using novel monoclonal antibodies increase the efficacy of chemo- and immune-therapies. We will test this assumption under three major sets of experiments: (i) elucidate the molecular mechanisms by which doppel activates neoangiogenesis and tumor progression in a spontaneous model of non-small cell lung carcinoma (NSCLC); (ii) assess the pharmacokinetics, pharmacodynamic and antitumor efficacy of anti-Doppel mAbs in KrasLSL-G12D;p53Frt/FRT mice in combination with chemotherapeutics; and (iii) assess how Dplhi-TECs control lung tumor immune microenvironment. This project has both basic and translational applicability, because we will understand the biology of Dplhi-TECs in tumor microenvironment as well use construct new mAbs to block this novel molecular target that has no known roles in physiological angiogenesis.

项目总结