Imaging and Overcoming Hypoxia-Induced Resistance in Metastatic Ovarian Cancer

描述（由申请人提供） 摘要：尽管在癌症的检测和治疗方面已经取得了很大的进展，但播散性转移癌仍然是晚期癌症患者死亡的主要原因。卵巢癌就是这样一种疾病，90%的死亡病例都是由显微镜下难以观察的病变引起的，这些病变通常会生长而无法抵抗治疗。卵巢癌是特别致命的，由于缺乏早期症状，其倾向于广泛覆盖整个腹部的组织和器官，具有隐匿性转移性疾病。令人沮丧的是，关于这些微观病变如何抵抗体内治疗，由于其广泛的性质和亚临床尺寸，知之甚少。缺氧，称为缺氧，是癌症治疗抵抗的主要原因，并且可能是抵抗性卵巢疾病的原因。这项新的创新者提案的目标是通过开发一种新的显微镜和平移成像方法来克服缺氧诱导的耐药性，以对抗转移性疾病。这个基于成像的平台将使用三种独立且高度互补的方法来了解治疗反应并克服低氧治疗阻力。将开发一种新的多模式高光谱显微内窥镜，以解决体内微转移病灶可视化的挑战，并将专门针对卵巢微转移缺氧状态和对治疗的反应进行成像。为了绘制缺氧和治疗反应之间的确切关系，我们将使用微转移性卵巢癌的3D体外模型进行高通量，显微镜，多参数可视化实验。此外，为了克服缺氧诱导的治疗抗性，我们将开发一种不依赖氧和肿瘤定位的光动力治疗方案，首先在体外进行测试，然后使用显微内窥镜平台在体内进行翻译和可视化。通过自下而上建立我们对治疗反应和耐药性的知识，这些组合方法形成了一种新的创新方法的基础，以了解并最终击败耐药微转移性疾病。 公共卫生相关性：转移性癌症往往是致命的，这是由于许多微小病变的扩散，这些病变可以生长成耐药性。该提案的目标是通过一种创新的微尺度可视化方法来解决卵巢癌治疗耐药性的主要因素，该方法不仅可以检测和可视化微转移治疗反应，而且还可以通过新的治疗方案克服治疗耐药性。通过建立对这些小的和逃避性病变的理解，并利用这些知识来击败耐药疾病，该提案旨在显着改善晚期转移性癌症患者的生活。

DESCRIPTION (Provided by the applicant) Abstract: Although much progress has been made in detecting and treating cancer, disseminated metastatic cancer remains the leading cause of death in patients with advanced stage carcinoma. Ovarian cancer is such a disease, with 90% of all fatalities arising from microscopic, difficult-to-visualize lesions that often grow to resist treatment. Ovarian cancer is particularly deadly due to a lack of early symptoms and its propensity to extensively coat the tissues and organs throughout the abdomen with occult metastatic disease. Frustratingly little is known regarding how these microscopic lesions resist treatment in vivo due to their widespread nature and sub-clinical size. A lack of oxygen, known as hypoxia, is a major cause of treatment resistance in cancer, and is likely responsible for resistant ovarian disease. The goal of this New Innovator proposal to is overcome hypoxia-induced resistance by developing a new microscopic and translational imaging approach for battling metastatic disease. This imaging-based platform will use three independent and highly complementary methods to understand treatment response and overcome hypoxic treatment resistance. A new multimodal hyperspectral microendoscope will be developed to address the challenge of visualizing micrometastatic lesions in vivo and wil be specificaly tailored to image both ovarian micrometastatic hypoxic state and response to treatment. To map the exact relationship between hypoxia and therapeutic response, we will use a 3D in vitro model of micrometastatic ovarian cancer to carry out high-throughput, microscopic, multiparametric visualization experiments. Furthermore, to overcome hypoxia-induced treatment resistance, we will develop an oxygen-independent and tumor-localizing photodynamic therapy regimen, first to be tested in vitro, and then translated and visualized in vivo using the microendoscopy platform. By building our knowledge of treatment response and resistance from the bottom up, these combined methods form the foundation of a fresh, innovative approach towards understanding and ultimately defeating treatment-resistant micrometastatic disease. Public Health Relevance: Cancer that becomes metastatic is too often fatal due to the spread of numerous microscopic lesions that can grow to become treatment resistant. The goal of this proposal is to address a major contributor to treatment resistance in ovarian cancer through an innovative microscale visualization approach that not only detects and visualizes micrometastatic treatment response, but also overcomes treatment resistance with new therapeutic regimens. By building an understanding of these small and evasive lesions, and using this knowledge to defeat treatment-resistance disease, this proposal aims to significantly improve the lives of patients suffering from advanced metastatic cancer.