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）：乳腺癌最常见地转移到骨骼和骨化骨转移的治疗方法上。量身定制的癌腺病毒是选择性地复制肿瘤细胞的新型抗癌药，具有巨大的治疗潜力，但在临床环境中的疗效有限。我们已经证明，通过重复腺病毒的有效肿瘤严重取决于原发性腺病毒受体的肿瘤表达。许多研究表明，原代癌细胞表达较低水平的coxsackievievivirus和腺病毒受体，CAR，并且受腺病毒感染不佳。此外，在非癌组织上的汽车在非癌组织上的广泛分布构成了选择性递送复制腺病毒以在全身给药后传播乳腺癌细胞的障碍。这两个问题表明，对复制选择性腺病毒的修饰允许对靶癌细胞的有效和选择性的与CAR无关的感染，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，可以通过工程来提供治疗转基因来增强复制选择性腺病毒的功效。我们建议用分泌的治疗蛋白将复制的腺病毒武装，并在局部骨微环境-Osteoprotegerin（OPG）中具有独特的作用机理，可抑制骨骼的吸收。我们假设拥有OPG武装的复制选择性腺病毒将通过抑制整骨骨骼的吸收并从而减轻肿瘤负担，从而直接通过闭塞和间接地消除乳腺癌的骨转移。综上所述，我们建议将两种不同的策略结合起来，以提高复制腺病毒治疗乳腺癌骨转移的功效。第一个具体的目的是构建一种表达OPG的对流式修饰，武装复制的腺病毒。第二个具体目的是评估在体外进行的疗效，武装腺病毒的疗效。第三个具体目的是评估体内托管，武装复制腺病毒的疗效。这将确定这种新型药物治疗人类乳腺癌骨转移的治疗潜力。