An Armed Oncolytic Adenovirus Targeting Bone Metastasis

一种针对骨转移的武装溶瘤腺病毒

• 批准号: 6987570
• 负责人: PREM SETH
• 金额: $ 13.16万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987570
• 关键词: Adenoviridae; athymic mouse; biotechnology; bone neoplasms; breast neoplasms; growth factor receptors; histopathology; human genetic material tag; metastasis; neoplasm /cancer remission /regression; neoplasm /cancer transplantation; osteoclasts; physiologic bone resorption; recombinant virus; technology /technique development; tissue /cell culture; transfection /expression vector; transforming growth factors; virus replication

DESCRIPTION (provided by applicant): Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. The majority of patients with advanced breast cancer will develop bone metastasis resulting in bone destruction causing severe bone pain and pathological fractures. The goal of this proposal is to develop a therapeutic approach that will destroy the primary tumor, and inhibit the bone metastasis. We will combine the oncolytic effects of an adenoviral vector along with selective expression of soluble form of TGFbeta receptor II fused with Fc (sTbetaRIIFc). TGFbeta pathway is an attractive target because high levels of TGFbeta protein enhance tumor invasion and bone metastasis. It is hypothesized that in the adenoviral vector 01/07sTbetaRIIFc, viral backbone will be oncolytic to the tumor cells and the vector-mediated production of sTbetaRIIFc and secretion into the blood will block the effects of TGFbeta. Aim 1). To investigate 01/07sTbetaRIIFc replication, 01/07sTbetaRIIFc-mediated sTbetaRIIFc production and inhibition of osteoclast formation in vitro. Various breast cancer cells and normal human cells will be infected with 01/07sTbetaRIIFc and analyzed for viral replication and sTbetaRIIFc production. The effect of sTbetaRIIFc expression on the formation of osteoclast cells responsible for bone resorption will be investigated. Aim 2). To investigate 01/07sTbetaRIIFc-mediated inhibition of bone metastasis and osteolysis in human breast cancer xenograft models in vivo. MDA-MB-231 cells will be used to produce subcutaneous tumors in nude mice. The 01/07sTbetaRIIFc will be injected into the tumors and viral replication, and the production and release of sTbetaRIIFc into the blood will be investigated. The adenoviral distribution in non-tumor organs and a set of liver enzymes, cytokines, and chemokines will be examined. To evaluate bone metastasis, animals bearing subcutaneous tumors will be injected with MDA-MB-231 cells into the left cardiac ventricle that results in bone metastasis. Recombinant viral vector will be injected into the subcutaneous tumors and radiographic measurements of osteolytic lesion area, microCT scan to quantify osteolysis, and histomorphometric analysis of the bones to quantify the tumor burden will be investigated.

描述（由申请人提供）：在美国，每年有近 200, 000 名女性被诊断患有乳腺癌。大多数晚期乳腺癌患者会发生骨转移，导致骨质破坏，导致严重的骨痛和病理性骨折。该提案的目标是开发一种能够破坏原发肿瘤并抑制骨转移的治疗方法。我们将把腺病毒载体的溶瘤作用与与 Fc 融合的可溶性 TGFbeta 受体 II (sTbetaRIIFc) 的选择性表达结合起来。 TGFbeta 途径是一个有吸引力的靶点，因为高水平的 TGFbeta 蛋白可增强肿瘤侵袭和骨转移。据推测，在腺病毒载体01/07sTbetaRIIFc中，病毒骨架将对肿瘤细胞具有溶瘤作用，并且载体介导的sTbetaRIIFc的产生和分泌到血液中将阻断TGFbeta的作用。目标1）。体外研究 01/07sTbetaRIIFc 复制、01/07sTbetaRIIFc 介导的 sTbetaRIIFc 产生以及破骨细胞形成的抑制。各种乳腺癌细胞和正常人类细胞将被 01/07sTbetaRIIFc 感染，并分析病毒复制和 sTbetaRIIFc 的产生。将研究 sTbetaRIIFc 表达对负责骨吸收的破骨细胞形成的影响。目标2）。研究 01/07sTbetaRIIFc 介导的人乳腺癌异种移植模型体内骨转移和骨溶解的抑制作用。 MDA-MB-231细胞将用于在裸鼠中产生皮下肿瘤。 01/07sTbetaRIIFc将被注射到肿瘤中并进行病毒复制，并且将研究sTbetaRIIFc的产生和释放到血液中。将检查非肿瘤器官中的腺病毒分布以及一组肝酶、细胞因子和趋化因子。为了评估骨转移，将带有皮下肿瘤的动物的左心室注射 MDA-MB-231 细胞，从而导致骨转移。将重组病毒载体注射到皮下肿瘤中，并对溶骨性病变区域进行放射线测量、微CT扫描以量化骨质溶解，以及对骨骼进行组织形态学分析以量化肿瘤负荷。