Elution of a Small Molecule from a Bio Ceramic Collagen Bone Graft Device Heals Bone while InhibitingBreast Cancer Bone Metastases

项目概要： 在70%的原发转移性乳腺癌患者中，骨生长对良好预后至关重要 有骨转移，或在美国每年约115，000名新患者。溶解性病变，或 骨中的空隙缺损是由肿瘤细胞导向的骨坏死骨重建引起的局部骨破坏引起的， 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，并包括稳定由骨形成的缺损， 肿瘤不幸的是，越来越多的患者由于无法进行植入而面临植入失败的风险。 硬件或骨水泥，以促进骨形成。由于高失败率和增加的病人 在美国每年的医疗保健支出中，溶解性病变占大约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/或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。潜在的未填充的骨缺损可以 导致植入物松动和机械稳定性丧失。增长因素已成为一个受欢迎的选择， 促进骨骼愈合。然而，这些疗法，如BMP-2（Infuse®）和PTH（Forteo®）， 对癌症患者的风险，有些已被禁止使用或给予黑盒警告FDA 对于活动性肿瘤患者或有肿瘤病史的患者。特别是，BMP-2与 正在接受X射线放射治疗或患有未检出的新生肿瘤的患者的肿瘤风险增加。 为了满足这一未满足的需求，Zetagen Therapeutics，Inc.，一家纽约的再生医学初创公司 正在商业化纳洛芬™骨移植物，这是一种新的组合产品，具有证明的能力， 通过诱导成骨同时抑制癌细胞的局部生长来治疗溶解性病变。基于 发现了一种新的骨生长分子途径，纳洛芬通过局部诱导成骨， 植入含有阿片样物质的磷酸钙生物陶瓷/牛胶原基骨移植物 拮抗剂纳洛酮。如果得到验证，纳洛芬骨移植物将为临床医生提供急需的 治疗溶解性骨缺损和对抗残余肿瘤的解决方案， 大量且不断增长的乳腺癌骨转移患者。 该提案由三个AIM组成，旨在推动纳洛芬植骨获得FDA批准 使用标准的安全性、生物利用度和疗效评估：1）评估纳洛芬的安全性，2）测试 纳洛芬的生物利用度和3）证实纳洛芬骨移植物促进骨生长。如果成功， 本提案将证明纳洛芬植骨植入物的商业确认，并确定 为首次人体试验做准备的基础。

Project Summary: Bone growth is critical to a favorable prognosis in the 70% of de novo metastatic breast cancer patients that have skeletal metastases, or approximately 115,000 new patients per year in the US. Lytic lesions, or void-defects in the bone, result from local bone destruction caused by tumor cell-directed osteoclastic bone re- absorption and lead to pathologic fractures 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. Unfortunately, a growing population of patients are at risk for implant failure due to the inability of hardware or bone cement to promote bone formation. Because of high failure rates and increased patient survival, lytic lesions account for approximately $2-billion in US healthcare expenditures per year. Patients with breast cancer bone metastases (i.e. a skeletal related event) require surgical intervention to stabilize the tumor-directed defect using intra-medullar nails, total joint prostheses, and/or bone cement. However, hardware and bone cement don’t promote bone formation. The underlying unfilled bone defects can result in implant loosening and loss of mechanical stability. Growth factors have become a popular option to increase bone healing. However, these therapies, such as BMP-2 (Infuse®) and PTH (Forteo®), have safety risks for cancer patients and some have been contraindicated for use or given a black-box warning by the FDA for patients with active tumor or patients with history of tumor. In particular, BMP-2 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, Zetagen Therapeutics, Inc., a New York regenerative medicine startup is commercializing the Nalovent™ Bone Graft, a new combination product with a demonstrated ability to treat lytic lesions by inducing osteogenesis while inhibiting local growth of cancer cells. Based on the discovery of a novel molecular pathway for bone growth, Nalovent induces osteogenesis via the local implantation of a calcium phosphate bioceramic / bovine collagen-based bone graft that contains the opioid antagonist, naloxone. If validated, the Nalovent Bone Graft would empower clinicians with a much-needed solution to heal lytic bone defects 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 three AIMs meant to drive the Nalovent Bone Graft towards FDA approval using standard safety, bioavailability, and efficacy assessments: 1) Assess the safety of Nalovent, 2) Test the bioavailability of Nalovent and 3) Validate that the Nalovent Bone Graft promotes bone growth. If successful, this proposal will demonstrate commercial validation for the Nalovent Bone Graft implant and establish the foundation for the preparation for first-in-man trials.