Targeting the vascularity for delivery of inhibitors of metastasis in ovarian cancer

 描述（由申请人提供）：上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤。尽管最初的反应率为80%，但5年生存率仅为15%，因为大多数患者会复发。在复发的情况下，与微转移和化疗耐药的共同表现限制了可用治疗方案的价值。因此，为了提高生存率，关键是要了解机制，促进复发和转移，并开发新的方法来防止it. To实现这一点，阐明细胞的起源和调控过程的转移是必要的。我们提出，在EOC中，转移潜力仅限于具有固有可塑性、干细胞性和间充质/迁移表型的癌细胞亚部分：间充质癌干细胞（mCSC）。我们证明了mCSC起源于EOC干细胞，并且其产生强烈受TGF β 1/Twist 1轴驱动，而不依赖于经典的TGF β 1/Smad通路。因此，我们的中心假设是，在肿瘤微环境中特异性靶向和控制释放TGFβ抑制剂将有效阻断TGF β 1/Twist 1通路，以防止mCSC的形成并降低转移性肿瘤负荷。我们已经开发了一种包覆有RGD肽（Arg-Gly-Asp）的纳米级脂质体聚合物凝胶（nLGs）平台，其靶向在肿瘤相关的新血管系统中高度表达的细胞粘附分子α v β 3整联蛋白。重要的是，除了赋予特异性之外，所提出的nLG递送平台还提供了用于TGFβ抑制的协同双管齐下的方法。我们的具体目标是：目标1。探讨TGF β 1/PKC通路在卵巢癌间质/迁移干细胞Twist 1稳定化和生成中的作用。表征肿瘤新生血管靶向递送系统，用于同时抑制TGF β加工和分泌以预防转移;目的3.确定具有包封的TGF β 1抑制剂的α v β 3定向纳米颗粒在EOC体内模型中的功效。在完成这些研究后，我们将更好地了解EOC转移性疾病的发生和建立，我们将提供一种新的治疗方法，使用安全和有前途的颗粒输送平台来降低转移性肿瘤负荷。有了这个新的观点，我们将能够创造一个更好的管理计划，以减少转移负荷，提高患者的生存在这个致命的妇科恶性肿瘤。

 DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite an initial 80% response rate, the 5-year survival rate is only 15% as most patients develop recurrence. In the recurrent setting, co-presentation with micrometastasis and chemoresistance limits the value of available treatment options. Therefore, to improve survival it is critical to understand the mechanisms that promote recurrence and metastasis and to develop novel approaches to prevent it. To achieve this, elucidation of the cellular origin and regulatory processes governing metastasis is a requisite. We propose that in EOC, metastatic potential is limited to a subfraction of cancer cells with inherent plasticity, stemness, and a mesenchymal/migratory phenotype: the mesenchymal cancer stem cells (mCSCs). We show evidence that mCSCs originate from EOC stem cells and that its generation is strongly driven by the TGFß/Twist1 axis independent of the classical TGFß/Smad pathway. Therefore, our central hypothesis is that specific targeting and controlled release of TGFβ inhibitors in the tumor microenvironment will potently block the TGFß/Twist1 pathway to prevent the formation of mCSCs and decrease metastatic tumor burden. We have developed a nanoscale liposomal polymeric gel (nLGs) platform coated with the RGD peptide (Arg-Gly-Asp), which targets the cellular adhesion molecule, avß3 integrins that are highly expressed in tumor-associated neovasculature. Importantly, in addition to conferring specificity, the proposed nLG delivery platform also provides a synergistic two-prong approach for TGFβ inhibition. Our specific aims are: Aim 1. To determine the role of TGFß /PKC pathway in Twist1 stabilization and generation of mesenchymal/migratory ovarian cancer stem cells; Aim 2. Characterization of tumor neovasculature-targeted delivery system for simultaneous inhibition of TGFß processing and secretion for prevention of metastasis; Aim 3. To determine the efficacy of avß3-directed nanoparticle with encapsulated TGFß inhibitor in an EOC in vivo model. Upon completion of these studies, we will have a better understanding of the initiation and establishment of metastatic disease in EOC and we will provide a novel therapeutic approach to decrease metastatic tumor burden using a safe and promising particulate delivery platform. With this new perspective, we will be able to create a better plan of management to decrease metastatic load and improve patient survival in this lethal gynecologic malignancy.