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取得了很大进展，但播散性转移癌仍然是晚期癌症患者的主要死亡原因。卵巢癌就是这样一种疾病，所有死亡的90%都是由难以观察到的微小病变引起的，这些病变往往会生长到无法接受治疗的地步。卵巢癌尤其致命，因为它缺乏早期症状，而且倾向于在整个腹部的组织和器官中广泛覆盖隐匿性转移疾病。令人沮丧的是，由于这些微小病变的广泛性和亚临床规模，人们对它们如何在体内抵抗治疗知之甚少。缺氧，也就是所谓的缺氧，是癌症耐药的主要原因，也可能是耐药卵巢疾病的原因。这项新的创新者提案的目标是通过开发一种新的显微和翻译成像方法来对抗转移疾病，以克服缺氧诱导的耐药性。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和克服低氧治疗抵抗。将开发一种新的多模式高光谱显微内窥镜，以解决在活体内可视化微转移病变的挑战，并将专门定制以成像卵巢微转移的低氧状态和治疗反应。为了描绘缺氧和治疗反应之间的确切关系，我们将使用卵巢微转移的3D体外模型进行高通量、显微、多参数的可视化实验。此外，为了克服低氧诱导的治疗耐药性，我们将开发一种氧非依赖性和肿瘤定位的光动力学治疗方案，首先进行体外测试，然后利用显微内窥镜平台进行体内翻译和可视化。通过自下而上地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、创新的方法的基础，以了解并最终击败耐药微转移疾病。 公共卫生相关性：由于大量微小病变的扩散，转移的癌症往往是致命的，这些病变可能会增长到对治疗产生抗药性。这项建议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贡献者，这种方法不仅可以检测和可视化微转移治疗反应，而且还可以用新的治疗方案克服治疗耐药性。通过建立对这些小的和回避的病变的理解，并利用这一知识来战胜耐药疾病，这项建议旨在显著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.