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

• 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
• 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

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.

有效治疗复发性上皮卵巢癌是主要未满足的公共卫生需求 传统化学疗法的患者反应率通常很低。重新利用药物是 由于新药物开发的财务和后勤限制，肿瘤学的越来越流行的战略越来越流行。 最近，抗寄生虫药物（例如甲苯达唑）已浮出水面，并显示 有望治疗多种类型的肿瘤。抗寄生虫药物，芬本唑和甲苯二唑在 苯咪唑类，已被FDA批准用于治疗人类的Pinworm和其他蠕虫感染 和动物数十年。这些药物对寄生虫而不是宿主的选择性由 寄生虫中葡萄糖摄取的不可逆转封锁，导致糖原消耗和变性 内质网和最终细胞死亡。此外，芬本唑和甲苯二唑都抑制 微管聚合和寄生虫的功能，但在人类或哺乳动物中不作用，由于差异键 残留物会产生一个无法访问的疏水口袋，抗寄生虫无法结合。 尽管这些似乎是寄生虫的作用机理，但其反癌的确切机制 人类细胞的影响尚不清楚。为了调查这个问题，我们通过衡量和 使用两种新型的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）的组合来量化肿瘤形态，脉管系统和密度的变化 可以准确评估光学断层扫描（FLOT），作用机理和治疗作用。 体内。该项目的主要目的是彻底评估抗寄生虫药物的抗癌作用 在使用OCT和FLOT的卵巢癌小鼠模型中。为了验证我们的假设并实现 该项目的目标，我们提出以下三个特定目标。目标1：优化校准 腹膜腹膜后肿瘤后肿瘤测量在卵巢癌异种移植小鼠模型中 与标准电子卡尺测量值相比，使用OCT和FLOT的Mebendazole使用。目标2：使用OCT 并进行卵巢癌异种移植物暴露后血管形态变化的特征 小鼠模型进行Mebendazole治疗。目标3：使用OCT和FLOT测量表面与深层 肿瘤细胞死亡并确定定量成像标记，以评估基于甲甲曲霉的抗癌治疗的功效。如果成功，该项目的结果将提供有关反癌的重要信息 Mebendazole以及令人信服的初步或临床前数据的影响，以支持研究项目 负责人（RPL）申请更全面的项目（即NIH R01或DOD CDMRP 2级赠款），以进一步 调查并确定将这种有希望的抗寄生虫药物应用于更多的最佳机制 在涉及人类受试者的临床研究或试验中有效治疗上皮卵巢癌。