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

抽象的。在此SBIR第一阶段应用程序中，我们的目标是演示我们的领先优势的概念证明 螯合剂预防芳香酶所致骨质疏松的潜在治疗作用 激素受体阳性乳腺癌绝经后妇女的AI治疗。 尽管人工智能治疗在无癌和总存活率方面有很大改善，但接受治疗的患者面临着 骨质疏松的风险，因为人工智能抑制雌激素的产生。事实上，AI骨骼毒性已经成为最大的 人工智能治疗中断的常见原因。目前，预防的治疗选择很少。 人工智能诱发的骨质疏松。双磷酸盐和地诺单抗(两种流行的骨质疏松症药物)具有保护作用； 然而，两者都有一个无法治疗的副作用，即颌骨坏死，以及其他有关 毒性大，治疗效果不佳。在这里，我们假设人工智能诱导的骨质疏松症可能是 由我们的螯合剂预防，对人工智能行动没有不利影响；该试剂能够针对新的 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 用于人工智能治疗的乳腺癌患者。这一假设得到了我们研究的支持，这些研究表明，我们的 螯合剂预防去卵巢(OVX)大鼠骨质丢失(绝经后骨质疏松模型) 雌激素缺乏)。利用这一发现开发治疗新药是合理的。 AI诱导的骨质疏松症，由于OVX和AI在导致雌激素方面的作用机制相似 缺乏和随之而来的骨丢失。这项技术的两项美国专利已授权给NanoMedic，一家 犹他大学(UU)创业公司，一直在拓宽技术应用并寻求 额外的专利保护。我们的目标是合成先导剂，并确定其预防效果。 去卵巢大鼠AI治疗后骨质疏松症的发生。具体地说：合成后，该试剂将在 AI处理的OVX大鼠，并与假手术组、OVX组和AI或 人工智能/双磷酸盐。将进行剂量-反应研究，以进一步证实治疗效果。 收集的骨骼样本(例如股骨、胫骨和脊椎)将通过以下方法检查其治疗效果 组织形态计量学方法和各种成像技术。血液样本也将进行雌激素检测。 水平，以确定该药物是否对AI治疗有任何不良影响，以及血清骨生物标记物 以评估该试剂的疗效。所有这些类型的实验程序都已在 我们的实验室。据我们所知，我们的实验室是唯一一个开发出一种新的螯合治疗方法的实验室 治疗人工智能引起的骨质流失。我们的团队在螯合药物发现、骨骼方面拥有多学科的专业知识 生物学和骨治疗评价。我们相信，这一阶段的研究将取得成功，并为 为接下来的第二阶段研究奠定基础-完成向FDA提交的调查性新药。 最终，我们的开发将为全球市场带来新的、有效的骨质疏松症辅助药物。

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.