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

有效治疗复发性上皮性卵巢癌是一个主要的，未满足的公共卫生需求， 传统的化疗对患者的反应率通常很低。重新使用药物是一种 由于新药开发的财务和后勤限制，肿瘤学中越来越流行的策略。 最近，抗寄生虫药物如甲苯咪唑作为重新用途的肿瘤药物浮出水面， 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， 苯并咪唑类，并已被FDA批准用于治疗人类的蛲虫和其他蠕虫感染 几十年来，动物这些药物对寄生虫而不是宿主的选择性解释如下： 不可逆地阻断寄生虫的葡萄糖摄取，导致糖原耗尽和 最终细胞死亡。此外，芬苯达唑和甲苯达唑均抑制 微管聚合和功能在寄生虫，但不是在人类或哺乳动物，由于差异的关键， 残基，其产生抗寄生虫药物不能结合的难以接近的疏水口袋。 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 使用两种新的高分辨率组织成像方法（包括光学相干断层扫描（OCT）和荧光层成像）的组合来量化肿瘤形态、脉管系统和密度的变化， 光学断层扫描（FLOT），药物作用机制和治疗效果可以准确地评估， vivo.本计画的主要目的是彻底评估抗寄生虫药物的抗癌效果 在卵巢癌小鼠模型中使用OCT和FLOT。为了验证我们的假设， 为了实现这一目标，我们提出了以下三个具体目标。目标1：优化校准 在卵巢癌异种移植小鼠模型中的腹膜内尸检后肿瘤测量 甲苯咪唑使用OCT和FLOT相比，标准的电子卡尺测量。目的2：使用OCT 和FLOT来表征暴露于卵巢癌异种移植物后血管形态的变化 小鼠模型给予甲苯咪唑治疗。目的3：使用OCT和FLOT测量浅表与深部 肿瘤细胞死亡和鉴定定量成像标记物以评价基于甲苯咪唑的抗癌治疗的功效。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可信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于更多 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。

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.