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

项目总结： 骨生长对70%初发转移性乳腺癌患者的良好预后至关重要 在美国，每年大约有115,000名新患者。溶解性病变，或 空洞-骨缺损，由肿瘤细胞导向的破骨细胞性骨修复引起的局部骨破坏所致。 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，并涉及稳定由 肿瘤。不幸的是，越来越多的患者面临着种植失败的风险，这是由于无法 硬件或骨水泥，以促进骨形成。因为高故障率和增加的病人 存活、溶解的病变每年约占美国医疗保健支出的20亿美元。 乳腺癌骨转移患者(即骨骼相关事件)需要手术治疗。 使用髓内钉、全关节假体和/或骨水泥固定肿瘤导向的缺损区。 然而，硬件和骨水泥并不能促进骨形成。潜在的未填充骨缺损会 导致种植体松动和失去机械稳定性。增长因素已成为一种流行的选择 促进骨骼愈合。然而，这些疗法，如BMP-2(Inuse®)和PTH(Forteo®)是安全的 对癌症患者的风险，其中一些已被FDA禁止使用或给予黑盒警告 适用于活动性肿瘤患者或有肿瘤病史的患者。特别是，BMP-2已被认为与 正在接受X-射线治疗或拥有新生的未发现肿瘤的患者的肿瘤风险增加。 为了回应这一未得到满足的需求，纽约再生医学初创公司Zetgen Treateutics，Inc. 正在商业化纳洛芬™骨移植，这是一种新的组合产品，具有被证明的能力 通过在抑制癌细胞局部生长的同时诱导成骨来治疗溶骨性病变。基于 发现一种新的骨生长分子途径，纳洛芬通过局部诱导成骨 含阿片类药物的磷酸钙生物陶瓷/牛胶原基骨移植 拮抗剂，纳洛酮。如果得到验证，Nalovent骨移植将使临床医生能够获得急需的 解决方案，以修复溶解的骨缺损和抗击残留的肿瘤，以提供显着改善的结果 患有骨骼转移的乳腺癌患者的数量庞大且不断增长。 这项提案包括三个目标，旨在推动纳洛芬骨移植获得FDA的批准 使用标准的安全性、生物利用度和有效性评估：1)评估纳络酮的安全性，2)测试 Nalovent的生物利用度和3)验证Nalovent骨移植促进骨骼生长。如果成功， 该提案将展示纳洛文骨移植植入物的商业验证，并建立 为第一人试验的准备工作奠定了基础。

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.