Validation of a novel, adjuvant implant for post-metastatic skeletal lesions

项目摘要 骨生长对于70%的乳腺癌患者的良好预后至关重要， 转移，或在美国每年约175，000例患者。溶解性病变，或骨中的空隙， 从局部骨质破坏引起的肿瘤细胞的定向，骨钙素骨重吸收，并导致 病理性骨折和增加患者发病率。手术干预是必要的，以防止初始骨折 或其他骨骼相关事件，并且涉及稳定由肿瘤产生的缺陷。目前，失败率 对于因病理性骨折固定后存活超过1年的患者， 骨折由于高失败率和患者生存率的增加，溶胞性病变正在影响越来越多的 患者群体，每年在美国医疗保健支出中占约20亿美元。 乳腺癌骨转移（即骨骼相关事件）患者需要手术干预 使用髓内钉、全关节假体和骨水泥稳定肿瘤定向缺损。 然而，硬件和骨水泥不促进骨形成。生长因子已成为一种流行的 然而，这些疗法，如BMP 2（Infuse®）或PTH（Forteo®）， FDA对患有活动性肿瘤或接受过治疗的患者给予黑框警告 对于肿瘤。特别是，BMP 2与正在接受X-射线治疗的患者的肿瘤风险增加有关。 放射治疗或拥有未被发现的新生肿瘤。 为了满足这一未满足的需求，总部位于纽约的初创公司Fusologics，LLC 将纳洛芬™商业化，这是一种新型外科植入物，经证实能够通过以下方式治疗溶解性病变： 有效地生长骨骼和抑制癌细胞的局部生长。基于一本小说的发现 骨生长的分子途径，纳洛芬通过植入物的局部给药诱导骨生成 其包含包埋在胶原递送载体中的阿片样物质拮抗剂纳洛酮。如经验证，纳洛芬 将为临床医生提供急需的解决方案，以治愈溶解性病变并对抗残留肿瘤， 为大量且不断增长的乳腺癌患者提供显著改善的结局， 骨转移 该提案包括两个目的：1）优化局部周围的纳洛芬成骨植入物 抑制肿瘤生长，和2）在相关的体内研究中验证纳洛芬植入物。如果成功， 该提案将证明纳洛芬植入物的商业概念验证，并建立 为II期提案奠定了基础，以支持为人体试验做准备的剩余临床前开发。

Project Summary Bone growth is critical to a favorable prognosis in the 70% breast cancer patients that have skeletal metastases, or approximately 175,000 patients per year in the US. Lytic lesions, or voids in the bone, result from local bone destruction caused by tumor cell-directed, osteoclastic bone re-absorption and lead to pathologic fracture and increased patient morbidity. Surgical intervention is necessary to prevent initial fracture or other skeletal related events, and involves stabilizing the defect created by the tumor. Currently, failure rates with these interventions are 42% for patients who survive more than 1-year after fixation for pathological fracture. Because of the high failure rates and increased patient survival, lytic lesions are affecting a growing patient population and account for approximately $2 billion in US healthcare expenditure per year. Patients with breast cancer bone metastases (i.e. a skeletal related event) require surgical intervention that stabilizes the tumor-directed defect using intra-medullar nails, total joint prostheses and bone cement. However, hardware and bone cement don't promote bone formation. Growth factors have become a popular option to increase bone healing, however, these therapies, such as BMP2 (Infuse®) or PTH (Forteo®) have been given a black-box warning by the FDA for patients with active tumor or patients who have been treated for tumor. In particular, BMP2 has been associated with increased tumor risk in patients who are undergoing X- radiation therapy or possess nascent undetected tumor. In response to this unmet need, Fusologics, LLC, a New York-based startup company is commercializing Nalovent™, a novel surgical implant with demonstrated ability to treat lytic lesions by effectively growing bone and inhibiting local growth of cancer cells. Based on the discovery of a novel molecular pathway for bone growth, Nalovent induces osteogenesis via the local administration of an implant that contains the opioid antagonist, naloxone, embedded in a collagen delivery vehicle. If validated, Nalovent would empower clinicians with a much-needed solution to heal lytic lesions and fight residual tumor in order to deliver significantly improved outcomes to the large and growing population of breast cancer patients with skeletal metastases. This proposal consists of two aims: 1) optimization of the Nalovent osteogenic implant around local inhibition of tumor growth, and 2) validation of the Nalovent implant in relevant in vivo studies. If successful, this proposal will demonstrate commercial proof-of-concept for the Nalovent implant and establish the foundation for a Phase II proposal to support remaining preclinical development in preparation for human trials.