Inhibition of matrix proteases to sensitize medulloblastoma cells to radiation

抑制基质蛋白酶使髓母细胞瘤细胞对辐射敏感

• 批准号: 8211080
• 负责人: JASTI S. RAO
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211080
• 关键词: Address; Adhesions; Adult; Apoptosis; Area; Astrocytoma; Attention; Back; Basic Science; Behavior; Brain; Brain Neoplasms; Cells; Cerebellum; Cerebrum; Child; Clinical; Development; Disease; Dose; Enzymes; Excision; External Beam Radiation Therapy; Gelatinase A; Gelatinase B; Genetic Materials; Glioma; Goals; Growth; Human; Immigration; Immune response; In Vitro; Infant; Infiltration; Intracranial Neoplasms; Invaded; Lead; Learning; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Memory; Messenger RNA; Metalloproteases; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Neuraxis; Neuronal Differentiation; Nude Mice; Operative Surgical Procedures; Patients; Peptide Hydrolases; Plasmid Cloning Vector; Plasminogen Activator; Primitive Neuroectodermal Tumor; RNA Interference; Radiation; Radiation therapy; Recurrence; Relapse; Resistance; Small Interfering RNA; Staging; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Urokinase; Urokinase Plasminogen Activator Receptor; Vertebral column; angiogenesis; base; cancer cell; cell growth; cellular targeting; chemotherapy; disability; emotional adjustment; gene therapy; improved; in vitro Model; in vivo; in vivo Model; irradiation; killings; medulloblastoma; medulloblastoma cell line; migration; neoplastic cell; neurosurgery; novel therapeutic intervention; outcome forecast; prevent; research study; response; social; treatment strategy; tumor; tumor growth; tumor progression; vector

DESCRIPTION (provided by applicant): Medulloblastomas, which belong to a group of primitive neuroectodermal tumors, are invasive tumors with predominant neuronal differentiation. Despite technological advances in neurosurgery, chemotherapy and radiation therapy, the prognosis for patients with these tumors remains variable and is relatively poor in infants and adult patients with metastatic disease. The traditional treatments are also toxic and can lead to long-term disabilities. Therefore new strategies are needed to prevent treatment related morbidity in these patients. One avenue possibly worth exploring further is the use of inhibition of matrix enzymes that contribute to collateral damage after therapeutic irradiation. This approach may also prevent clinical progression of the tumor by thwarting the invasive infiltration that characterizes glioma growth. A significant association of urokinase plasminogen activator (uPA) and matrix metalloprotease-9 (MMP-9) expression with survival and M-stage indicates that these proteases may modulate the survival of medulloblastoma patients. The levels of uPAR and MMP-9 expression and cellular invasiveness were increased in irradiated medulloblastoma cells. These findings led us to hypothesize inhibition of uPAR and MMP-9 by RNAi technology could be a potential therapeutic approach to improve the efficacy of radiotherapy in medulloblastoma patients. Specific Aim 1. Evaluate the effect of uPAR and MMP-9 inhibition and radiation alone and in combination on medulloblastoma cell growth, invasion and angiogenesis in both in vitro and in vivo models. Aim 1a. Determine the effect of puPAR, pMMP-9 and pUM in combination with radiation on the levels of uPAR and MMP-9 in medulloblastoma cell lines. Aim 1b. Determine the effect of puPAR, pMMP-9, pUM and radiation alone and in combination on the invasive behavior of human medulloblastoma cell lines in vitro models. Aim 1c. Evaluate the effect of puPAR, pMMP-9, pUM and radiation alone and in combination on cerebral angiogenesis in both in vitro and in vivo models. Aim 1d. Determine the optimal doses of puPAR, pMMP-9, pUM and radiation alone and in combination on pre-established intracranial tumor growth or invasiveness of human medulloblastoma cell lines injected intracerebrally in nude mice. Specific Aim 2. Determine the effect of puPAR, pMMP-9, pUM and radiation alone and in combination on the molecular mechanisms of proliferation, migration, adhesion and apoptosis in medulloblastoma cell lines. Aim 2a. Investigate the effect of puPAR, pMMP-9, pUM and radiation alone in combination on the molecular mechanisms of adhesion and migration in medulloblastoma cell lines compared to control/mock and scrambled vector (pSV) controls. Aim 2b. Determine the effect of puPAR, pMMP-9, pUM and radiation alone and in combination on the molecular mechanisms of proliferation in medulloblastoma cell lines compared with mock and pSV controls. Aim 2c. Evaluate the effect of puPAR, pMMP-9, pUM and in combination on the molecular mechanisms of apoptosis in medulloblastoma cell lines compared with mock and Psv controls. This combination of in vitro basic science experiments and translational in vivo studies will provide the basis for development of a new therapeutic approach to medulloblastoma tumors which are resistant to conventional radiotherapy. PUBLIC HELATH RELEVANCE: Medulloblastomas are one type of brain tumors that are found near the midline of the cerebellum. It is a type of brain tumor that occurs in infants and young children. After surgery, external radiation to the entire CNS (craniospinal irradiation, or CSI) is recommended to prevent the tumor from coming back in this area (recurrence, or relapse). Much attention has understandably been paid to the possible long-term complications of radiation therapy to the brain and spine of a growing child. These can include deficits in memory, learning, and social/emotional adjustment, and growth problems. A major goal for these patients is to develop treatment strategies that minimize the dose of radiation to the central nervous system. Gene therapy consists of the introduction of genetic material into diseased cellular targets to bring about therapeutic benefit. The present study explores the usefulness of gene therapy to inhibit protease expression in conjunction with radiation for killing of medulloblastoma cells with lower toxicity.

描述（申请人提供）：髓母细胞瘤属于一组原始神经外胚层肿瘤，是一种以神经元分化为主的侵袭性肿瘤。尽管神经外科，化学疗法和放射疗法的技术进步，预后