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 第一阶段应用中，我们的目标是展示我们的领先优势的概念证明 螯合剂作为预防芳香酶诱导的骨质疏松症的潜在治疗剂 抑制剂（AI）治疗患有激素受体阳性乳腺癌的绝经后妇女。 尽管人工智能疗法在无癌生存率和总体生存率方面显示出巨大的改善，但其治疗的患者仍面临着 骨质疏松症的风险，因为人工智能会抑制雌激素的产生。事实上，AI骨骼毒性已成为最严重的 AI 治疗停止的常见原因。目前，用于预防的治疗选择很少 AI引起的骨质疏松症。双膦酸盐和狄诺塞麦（两种流行的骨质疏松药物）具有保护作用； 然而，两者都有无法治疗的副作用，下颌骨坏死，以及其他问题 毒性和治疗效果不足。在这里，我们假设人工智能引起的骨质疏松症可能是 我们的螯合剂可以防止这种情况发生，并且不会对人工智能的行为产生不利影响；该代理能够瞄准新的 骨质疏松病原体，因此有可能成为当前骨质疏松药物的更好替代品 对于接受 AI 治疗的乳腺癌患者。我们的研究支持了这一假设，这些研究表明我们的能力 螯合剂可防止卵巢切除 (OVX) 大鼠（一种绝经后骨质疏松模型）骨质流失 雌激素缺乏）。利用这一发现来开发治疗新药是合理的 AI 诱发的骨质疏松症，由于 OVX 和 AI 引起雌激素的作用机制相似 缺乏和随之而来的骨质流失。这项技术的两项美国专利已授权给 NanoMedic， 犹他大学（UU）初创公司一直在拓宽技术应用并寻求 额外的专利保护。我们的目标是合成主要药物并确定其预防疾病的功效 AI 处理的 OVX 大鼠骨质减少的发育。具体来说：合成后，将在以下方面对代理进行评估： AI 治疗的 OVX 大鼠，并与假 OVX、OVX 和用 AI 或 OVX 治疗的大鼠进行比较 AI/双膦酸盐。将进行剂量反应研究以进一步确认治疗效果。 收集的骨骼样本（例如股骨、胫骨和椎骨）将通过以下方法检查治疗效果： 组织形态测量方法和各种成像技术。血液样本还将检测雌激素 水平以确定药物是否对 AI 治疗以及血清骨生物标志物有任何不利影响 以便评价药剂的功效。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 用于人工智能引起的骨质流失。我们的团队在螯合药物发现、骨 生物学和骨治疗评估。我们相信这一阶段的研究将会成功，并奠定 为以下 II 期研究奠定基础 - 完成向 FDA 提交研究性新药。 最终，我们的开发将为全球市场带来新的、有效的骨质疏松辅助药物。