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

从生物陶瓷胶原骨移植装置中洗脱小分子可以治愈骨骼，同时抑制乳腺癌骨转移

• 批准号: 10525302
• 负责人: Bryan Samuel Margulies
• 金额: $ 25万
• 依托单位: ZETAGEN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525302
• 关键词: Acute; Address; Animals; BMP2 gene; Binding; Biological Assay; Biological Availability; Bone Growth; Bone Transplantation; Bone neoplasms; Breast Cancer Patient; Canada; Cancer Cell Growth; Cancer Patient; Cattle; Cell Count; Ceramics; Clinical Research; Collagen; Complication; Contracts; Coupled; Data; Defect; Devices; Disease remission; Failure; Forteo; Foundations; Fracture; Goals; Growth Factor; Guidelines; Health; Health Expenditures; Image; Implant; Joint Prosthesis; Kinetics; Label; Lateral; Lead; Lytic; Lytic Lesion; Malignant Bone Neoplasm; Mechanics; Medical Device; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Modeling; Molecular; Morbidity - disease rate; Mus; Nail plate; Naloxone; Neoplasm Metastasis; New York; Operative Surgical Procedures; Opioid Antagonist; Oryctolagus cuniculus; Osteoclasts; Osteogenesis; Pathological fracture; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Population; Preparation; Process; Prognosis; Radiation therapy; Recording of previous events; Recurrence; Regenerative Medicine; Residual Tumors; Risk; Rod; Roentgen Rays; Safety; Sterilization; Testing; Therapeutic; Tissues; Toxic effect; Tumor Volume; Validation; Vendor; Vertebral column; Work; absorption; allogenic bone transplantation; base; biomaterial compatibility; bone; bone healing; calcium phosphate; cancer risk; cytotoxicity; efficacy evaluation; efficacy study; fighting; first-in-human; genotoxicity; healing; implantation; improved outcome; irritation; malignant breast neoplasm; methionine-enkephalin receptor; monocyte; mouse model; neoplastic cell; novel; patient population; phase 1 study; pre-clinical; preclinical study; prevent; product development; prototype; recruit; response; safety study; skeletal-related events; small molecule; systemic toxicity; tibia; tumor; tumor growth

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.

项目概要： 骨生长对于 70% 的新发转移性乳腺癌患者的良好预后至关重要 患有骨骼转移的患者，或美国每年约有 115,000 名新患者出现溶解性病变。 骨中的空隙缺陷，是由肿瘤细胞定向破骨细胞骨重建引起的局部骨破坏造成的。 吸收并导致病理性骨折并增加患者发病率，因此需要进行手术干预。 以防止初始骨折或其他骨骼相关事件，并涉及稳定由骨折引起的缺陷 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。 硬件或骨水泥促进骨形成由于失败率高且患者增加。 每年，溶解性病变在美国医疗保健支出中约占 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/或骨水泥稳定肿瘤导向的缺损。 然而，硬件和骨水泥不会促进骨形成，从而可以促进潜在的未填充骨缺损。 导致种植体松动和机械稳定性丧失的生长因子已成为一种流行的选择。 然而，BMP-2 (Infuse®) 和 PTH (Forteo®) 等疗法具有安全性。 癌症患者存在风险，有些已被 FDA 禁止使用或发出黑框警告 对于患有活动性肿瘤或有肿瘤病史的患者，特别是BMP-2与相关。 正在接受 X 射线治疗或患有未检测到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，纽约再生医学初创公司 Zetagen Therapeutics, Inc. 正在将 Nalovent™ 骨移植物商业化，这是一种新的组合产品，已被证明能够 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。 Nalovent 发现了一种新的骨生长分子途径，通过局部诱导成骨 植入含有阿片类药物的磷酸钙生物陶瓷/牛胶原蛋白骨移植物 拮抗剂纳洛酮如果得到验证，Nalovent 骨移植物将赋予人们急需的力量。 治愈溶解性骨缺损并对抗残留肿瘤的解决方案，以显着改善预后 患有骨骼转移的乳腺癌患者数量庞大且不断增长。 该提案包括三个目标，旨在推动 Nalovent 骨移植获得 FDA 批准 使用标准安全性、生物利用度和功效评估：1) 评估 Nalovent 的安全性，2) 测试 Nalovent 的生物利用度以及 3) 验证 Nalovent 骨移植物促进骨骼生长 如果成功， 该提案将展示 Nalovent 骨移植植入物的商业验证，并建立 为首次人体试验的准备奠定了基础。