Armed Replicating Ad for Breast Cancer Bone Metastasis

乳腺癌骨转移的武装复制广告

• 批准号: 7033138
• 负责人: Joanne T Douglas
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-08 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033138
• 关键词: Adenoviridae; athymic mouse; biotherapeutic agent; bone neoplasms; breast neoplasm /cancer diagnosis; breast neoplasms; cell adhesion molecules; clinical research; human subject; immunoglobulin G; metastasis; neoplasm /cancer remission /regression; osteoprotegerin; osteosarcoma; pathologic bone resorption; virus receptors; virus replication

DESCRIPTION (provided by applicant): Breast cancer most commonly metastasizes to the skeleton and improvements in therapy for osteolytic bone metastases are required. Oncolytic adenoviruses tailored to replicate selectively with tumor cells are novel anticancer agents with great therapeutic potential but have shown limited efficacy in the clinical setting. We have demonstrated that efficient oncolysis by a replicating adenovirus is critically dependent on tumor expression of primary adenovirus receptors. A number of studies that have shown that primary cancer cells express low levels of the coxsackievirus and adenovirus receptor, CAR, and are poorly infected by adenoviruses. Moreover, the widespread distribution of CAR on noncancerous tissues presents an obstacle to the selective delivery of replicating adenoviruses to disseminated breast cancer cells upon systemic administration. These two concerns imply that modification of a replication-selective adenovirus to allow efficient and selective CAR-independent infection of target cancer cells could both improve the efficacy of the virus and reduce toxicity to normal cells. In addition, the efficacy of a replication-selective adenovirus could be enhanced by engineering it to deliver a therapeutic transgene. We propose to arm the replicating adenovirus with a secreted therapeutic protein, with a distinct mechanism of action within the local bone microenvironment - osteoprotegerin (OPG), which inhibits bone resorption. We hypothesize that a replication-selective adenovirus armed with OPG would eradicate bone metastases of breast cancer both directly, by oncolysis, and indirectly, by inhibiting osteoclastic bone resorption and thus reducing the tumor burden. Taken together, we propose to combine two distinct strategies to improve the efficacy of replicating adenoviruses for the treatment of bone metastases of breast cancer. The first specific aim is to construct a tropism-modified, armed replicating adenovirus expressing OPG. The second specific aim is to evaluate the efficacy of the tropism-modified, armed replicating adenovirus in vitro. The third specific aim is to evaluate the efficacy of the tropism-modified, armed replicating adenovirus in vivo. This will establish the therapeutic potential of this novel agent for the treatment of bone metastases of breast cancer in humans.

描述（由申请人提供）：乳腺癌最常转移至骨骼，需要改进溶骨性骨转移的治疗。专为与肿瘤细胞选择性复制而设计的溶瘤腺病毒是具有巨大治疗潜力的新型抗癌药物，但在临床环境中显示出的功效有限。我们已经证明，复制腺病毒的有效溶瘤作用严重依赖于原代腺病毒受体的肿瘤表达。多项研究表明，原发性癌细胞表达低水平的柯萨奇病毒和腺病毒受体 CAR，且不易被腺病毒感染。此外，CAR在非癌组织上的广泛分布对全身给药时选择性地将复制性腺病毒递送至播散性乳腺癌细胞构成了障碍。这两个问题意味着，对复制选择性腺病毒进行修饰，以允许对靶癌细胞进行有效和选择性的不依赖于 CAR 的感染，既可以提高病毒的功效，又可以降低对正常细胞的毒性。此外，复制选择性腺病毒的功效可以通过对其进行改造以传递治疗性转基因来增强。我们建议用一种分泌的治疗蛋白武装复制的腺病毒，该蛋白在局部骨微环境中具有独特的作用机制——骨保护素（OPG），可抑制骨吸收。我们假设携带 OPG 的复制选择性腺病毒可以通过溶瘤直接消除乳腺癌骨转移，并通过抑制破骨细胞骨吸收间接消除乳腺癌骨转移，从而减轻肿瘤负担。综上所述，我们建议结合两种不同的策略来提高复制腺病毒治疗乳腺癌骨转移的疗效。第一个具体目标是构建表达 OPG 的向性修饰的武装复制腺病毒。第二个具体目标是评估趋向性修饰的武装复制腺病毒在体外的功效。第三个具体目标是评估向性修饰的武装复制腺病毒在体内的功效。这将确立这种新药治疗人类乳腺癌骨转移的治疗潜力。