A therapeutic approach for potential prevention of aromatase inhibitor-induced bone loss

潜在预防芳香酶抑制剂引起的骨质流失的治疗方法

• 批准号: 9621018
• 负责人: GANG LIU
• 金额: $ 22.3万
• 依托单位: NANOMEDIC, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9621018
• 关键词: Adjuvant; Adverse effects; Aftercare; Animal Model; Aromatase; Aromatase Inhibitors; Biological Markers; Biology; Blood specimen; Bone Resorption; Bone necrosis; Breast Cancer Patient; Businesses; Chelating Agents; Chemical Structure; Clinical Management; Data; Deposition; Development; Dose; Drug Evaluation; Effectiveness; Electron Spin Resonance Spectroscopy; Enzymes; Estrogens; Excretory function; Face; Femur; Formulation; Foundations; Fracture; Free Radical Formation; Free Radicals; Functional disorder; Funding; Generations; Goals; Imaging technology; Immune system; Investigation; Investigational Drugs; Iron; Iron Chelating Agents; Iron Chelation; Jaw; Jaw Cancer; Lead; Legal patent; Malignant Neoplasms; Measures; Medicine; Metabolism; Methods; Modeling; Nervous system structure; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Osteoporosis prevention; Osteoporotic; Patients; Pharmaceutical Preparations; Phase; Postmenopausal Osteoporosis; Postmenopause; Prevention; Procedures; Rattus; Regulation; Reporting; Risk; Sampling; Serum; Skeleton; Small Business Innovation Research Grant; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Translating; Treatment Effectiveness; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Universities; Use Effectiveness; Utah; Woman; absorption; base; bisphosphonate; bone; bone loss; chelation; commercialization; comparative efficacy; drug development; drug discovery; hormone receptor-positive; malignant breast neoplasm; men; metalloenzyme; microCT; multidisciplinary; nonhuman primate; novel; novel therapeutics; osteoporotic bone; oxidative damage; pathogen; phase 1 study; phase 2 study; prevent; protective efficacy; response; skeletal; spine bone structure; therapeutic effectiveness; therapeutic evaluation; tibia

Abstract. In this SBIR Phase I application, our goal is to demonstrate proof of concept of our lead chelating agent as a potential therapeutic for the prevention of osteoporosis induced by aromatase inhibitor (AI) therapy in postmenopausal women with hormone-receptor-positive breast cancer. Although AI therapy shows great improvements in cancer-free and overall survival, its treated patients face a risk of osteoporosis, because AI inhibits estrogen generation. In fact, AI skeletal toxicity has become the most frequent reason for AI therapy discontinuation. Currently, there are very few therapeutic options for preventing AI-induced osteoporosis. Bisphosphonates and denosumab (two popular osteoporotic drugs) are protective; however both have an untreatable side-effect, osteonecrosis of the jaw, as well as other concerns regarding toxicity and inadequate therapeutic efficacy. Here, we hypothesize that AI-induced osteoporosis may be prevented by our chelating agent without adverse effects on AI actions; this agent is able to target new osteoporotic pathogens, hence having potential as a better alternative to current osteoporotic drugs for AI-treated breast cancer patients. This hypothesis is supported by our studies that show the ability of our chelating agent to prevent bone loss in ovariectomized (OVX) rats (a postmenopausal osteoporotic model due to estrogen deficiency). It is reasonable to exploit this finding toward the development of new drugs for treating AI-induced osteoporosis, due to the similarities of the OVX and AI mechanisms of actions in causing estrogen deficiency and consequent bone loss. Two US patents on this technology have been licensed to NanoMedic, a University of Utah (UU) startup company which has been broadening the technology application and seeking additional patent protection. Our aim is to synthesize the lead agent and define its efficacy for preventing osteopenic development in AI-treated OVX rats. Specifically: after synthesis, the agent will be evaluated in AI-treated OVX rats, and compared with rats that are sham-OVX, OVX, and OVX treated with AI or AI/bisphosphonate. A dose-response study will be conducted to further confirm the therapeutic efficacy. Collected bone samples (e.g., femur, tibia and vertebra) will be examined for treatment effectiveness using histomorphometric methods and various imaging technologies. Blood samples will also be tested for estrogen levels to determine whether the agent has any adverse effects on AI treatment, and for serum bone biomarkers in order to evaluate the agent's efficacy. All of these types of experimental procedures have been performed in our lab. To our best knowledge, our lab is the only one to develop a new kind of chelation therapeutic approach for AI-induced bone loss. Our team possesses multidisciplinary expertise in chelating drug discovery, bone biology, and bone therapeutic evaluation. We believe that this Phase I study will succeed, and lay the foundation for the following Phase II study - to fulfill an investigational new drug submission to the FDA. Ultimately, our development will bring new, effective osteoporotic adjuvant drugs to the global market.

抽象的。在此SBIR I阶段应用中，我们的目标是展示我们的铅的概念证明 螯合剂作为预防芳香酶诱导的骨质疏松症的潜在治疗方法 抑制剂（AI）治疗的绝经后妇女患有激素受体阳性乳腺癌。 尽管AI疗法在无癌症和整体生存方面表现出很大改善，但其治疗的患者面临 骨质疏松症的风险，因为AI抑制了雌激素的产生。实际上，AI骨骼毒性已成为最大的 AI治疗中断的经常原因。目前，预防的治疗选择很少 AI诱导的骨质疏松症。双膦酸盐和denosumab（两种流行的骨质疏松药）具有保护性。 但是，两者都有不可治疗的副作用，颌骨的骨坏死，以及其他有关 毒性和治疗功效不足。在这里，我们假设AI诱导的骨质疏松症可能是 我们的螯合剂阻止了对AI作用的不利影响；该代理能够针对新 骨质疏松病原体，因此具有当前骨质疏松药物的更好替代品的潜力 适用于AI治疗的乳腺癌患者。我们的研究证明了这一假设 防止卵巢切除（OVX）大鼠骨质流失的螯合剂（绝经后骨质疏松模型 雌激素缺乏）。利用这一发现来开发新药物是合理的 由于OVX的相似性和引起雌激素的作用机制，AI诱导的骨质疏松症 缺乏和随之而来的骨质流失。这项技术的两项美国专利已获得纳米医学的许可 犹他大学（UU）的初创公司一直在扩大技术应用和寻求 额外的专利保护。我们的目的是综合铅剂并确定其防止其功效 AI处理的OVX大鼠的骨质减少性发育。具体：合成后，将评估代理 AI治疗的OVX大鼠，并与用AI或AI治疗的shy-ovx，OVX和OVX大鼠进行比较 AI/双膦酸盐。将进行一项剂量反应研究，以进一步确认治疗功效。 将检查收集的骨样品（例如股骨，胫骨和椎骨） 组织形态学方法和各种成像技术。血液样本也将测试雌激素 确定药物是否对AI治疗和血清骨生物标志物有任何不利影响的水平 为了评估代理的功效。所有这些类型的实验程序均已在 我们的实验室。据我们所知，我们的实验室是唯一开发一种新型螯合治疗方法的实验室 用于AI引起的骨质流失。我们的团队拥有螯合药物发现的多学科专业知识 生物学和骨治疗评估。我们相信，我研究的阶段将成功，并放置 以下第二阶段研究的基金会 - 履行向FDA提交的调查新药物。 最终，我们的发展将为全球市场带来新的，有效的骨质疏松辅助药物。