Use of 3D Quantitative Optical Methods to Optimize Mebendazole Treatment of Ovarian Cancer

使用 3D 定量光学方法优化甲苯咪唑治疗卵巢癌

基本信息

批准号：
10662191
负责人：
Lauren Elizabeth Dockery
金额：
$ 18.08万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662191
关键词：
3-Dimensional Address Animals Antiparasitic Agents Autopsy Binding Blood Vessels Calibration Cancer Center Cancer Patient Cell Death Cells Centers of Research Excellence Clinical Clinical Research Clinical Trials Data Development Diagnosis Disease Disease remission Dose Electronics Endoplasmic Reticulum Engineering Enterobius Epithelial ovarian cancer Epithelium FDA approved Fenbendazole Fluorescence Future Glycogen Grant Human Hydrophobicity Image Imaging Techniques Imaging technology Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammals Mathematics Measurement Measures Medical Imaging Medical center Methods Microtubule Polymerization Modeling Morphology Oklahoma Oncology Optical Coherence Tomography Optical Methods Optical Tomography Ovarian Parasites Patient-Focused Outcomes Patients Penetration Pharmaceutical Preparations Public Health Recurrence Research Research Personnel Research Project Grants Research Support Resistance development Resolution Surface Survival Rate Testing Therapeutic Therapeutic Effect Tissue imaging Tissues Toxic effect Treatment Efficacy Tumor Tissue United States National Institutes of Health Variant Woman Xenograft procedure anti-cancer anticancer activity anticancer treatment benzimidazole biomarker evaluation biomedical imaging cancer therapy cancer type chemotherapy clinical application college density drug development drug mechanism drug repurposing effective therapy efficacy evaluation glucose uptake helminth infection high resolution imaging human subject imaging biomarker imaging modality improved in vivo innovation intraperitoneal meter mouse model neoplastic cell novel novel therapeutics pre-clinical predictive modeling quantitative imaging reconstruction response translational cancer research treatment response treatment strategy tumor tumor heterogeneity tumor microenvironment

项目摘要

Effective treatment for recurrent epithelial ovarian cancer is a major, unmet public health need as the response rates of the patients are often low with the traditional chemotherapy. Repurposing drugs is an increasingly popular strategy in oncology due to the financial and logistical constraints of new drug development. Recently, anti-parasitic drugs such as mebendazole have surfaced as repurposed oncology drugs and showed promise in treating multiple types of tumors. The anti-parasitic drugs, fenbendazole and mebendazole, are in the benzimidazole class and have been FDA-approved to treat pinworm and other helminthic infections in humans and animals for decades. The selectivity of these drugs for the parasite rather than the host is explained by irreversible blockade of glucose uptake in the parasite, leading to glycogen depletion and degeneration of the endoplasmic reticulum with eventual cell death. In addition, both fenbendazole and mebendazole inhibit microtubule polymerization and function in parasites but not in humans or mammals, owing to differential key residues, which create an inaccessible hydrophobic pocket to which the anti-parasitic drugs cannot bind. Although these seem to be the mechanisms of action in parasites, the exact mechanism of their anti-cancer effect in human cells is unknown. In order to investigate this issue, we hypothesize that by measuring and quantifying changes of tumor morphology, vasculature, and density using the combination of two novel highresolution tissue imaging methods including optical coherence tomography (OCT) and fluorescence laminar optical tomography (FLOT), drug mechanism of action and therapeutic effects can be accurately assessed in vivo. The primary objective of this project is to thoroughly evaluate the anti-cancer effects of anti-parasitic drugs in an ovarian cancer mouse model using OCT and FLOT. In order to validate our hypothesis and realize the objective of this project, we propose the following three specific aims. Aim 1: To optimize calibration of intraperitoneal post-necropsy tumor measurements in an ovarian cancer xenograft mouse model treated with mebendazole using OCT and FLOT compared to standard electronic caliper measurements. Aim 2: To use OCT and FLOT to characterize changes in blood vessel morphology upon exposure of an ovarian cancer xenograft mouse model to mebendazole treatment. Aim 3: To use OCT and FLOT to measure superficial versus deep tumor cell death and identify quantitative imaging markers for evaluating efficacy of mebendazole-based anticancer treatment. If successful, the results of this project will provide important information regarding anti-cancer effects of mebendazole and also the convinced preliminary or pre-clinical data to support the research project leader (RPL) to apply for a more comprehensive project (i.e., NIH R01 or DOD CDMRP Level 2 grant) to further investigate and determine the optimal mechanism of applying this promising anti-parasitic drug to more effectively treat epithelial ovarian cancer in the clinical study or trial involving human subjects.

复发性上皮性卵巢癌的有效治疗是一项未满足的重大公共卫生需求，因为传统化疗患者的反应率通常较低。重新利用药物是一种由于新药开发的财务和后勤限制，这一策略在肿瘤学领域日益流行。最近，甲苯咪唑等抗寄生虫药物作为新用途的肿瘤药物出现，并显示出有望治疗多种类型的肿瘤。抗寄生虫药物芬苯达唑和甲苯达唑属于苯并咪唑类，已获得 FDA 批准用于治疗人类蛲虫和其他蠕虫感染和动物几十年了。这些药物对寄生虫而不是宿主的选择性可以解释为不可逆地阻断寄生虫中的葡萄糖摄取，导致糖原耗尽和组织退化内质网最终导致细胞死亡。此外，芬苯达唑和甲苯咪唑均抑制由于差异关键，微管聚合和功能在寄生虫中起作用，但在人类或哺乳动物中不起作用残留物，形成抗寄生虫药物无法结合的难以接近的疏水袋。虽然这些似乎是寄生虫的作用机制，但它们抗癌的确切机制对人体细胞的影响尚不清楚。为了研究这个问题，我们假设通过测量和结合使用两种新型高分辨率组织成像方法（包括光学相干断层扫描 (OCT) 和荧光层流成像）来量化肿瘤形态、脉管系统和密度的变化光学断层扫描（FLOT）可准确评估药物作用机制和治疗效果体内。该项目的主要目标是彻底评估抗寄生虫药物的抗癌效果使用 OCT 和 FLOT 在卵巢癌小鼠模型中进行研究。为了验证我们的假设并实现针对这个项目的目标，我们提出以下三个具体目标。目标 1：优化校准卵巢癌异种移植小鼠模型的腹膜内尸检后肿瘤测量使用 OCT 和 FLOT 与标准电子卡尺测量结果比较甲苯咪唑。目标 2：使用 OCT 和 FLOT 来表征卵巢癌异种移植物暴露后血管形态的变化甲苯咪唑治疗小鼠模型。目标 3：使用 OCT 和 FLOT 测量浅层与深层肿瘤细胞死亡并确定定量成像标记物以评估基于甲苯咪唑的抗癌治疗的疗效。如果成功，该项目的结果将提供有关抗癌的重要信息甲苯咪唑的作用以及支持研究项目的令人信服的初步或临床前数据领导者（RPL）申请更全面的项目（即 NIH R01 或 DOD CDMRP 2 级拨款）以进一步研究并确定将这种有前途的抗寄生虫药物应用到更多领域的最佳机制在涉及人类受试者的临床研究或试验中有效治疗上皮性卵巢癌。