Heparanase in Tumor Progression, Metastasis and Chemoresistance

我们工作的长期目标是了解乙酰肝素酶是如何促进 研究肿瘤的侵袭性行为，并利用这一知识开发根治癌症的疗法。我们有 确认了乙酰肝素酶通过多种机制推动癌症进展、转移和 化疗耐药和肝素酶被确立为癌症治疗的可行靶点。此外，我们还催化了 旨在开发和测试新型抗乙酰肝素酶药物的合作努力，并展示了其 在癌症临床前模型中的有效性导致了目前正在进行的临床试验。现在的挑战是 最大化抗乙酰肝素酶治疗以增强其抗肿瘤效果；这一目标将通过 对乙酰肝素酶的作用机制有深入的了解。指导我们工作的首要假设是 乙酰肝素酶是癌症侵袭性表型的主要调节者，是一个重要的贡献者 许多癌症患者的不良结局，也是治疗的首要目标。这一假设得到了支持 研究主要集中在肿瘤细胞表达的乙酰肝素酶的影响上。我们最新的 这些发现揭示了两种新的、以前从未探索过的与肝素酶调节血管紧张素转换酶相关的机制。 癌症。我们发现：(I)非肿瘤(宿主)细胞在微环境中表达的肝素酶可以 实质上有助于肿瘤的进展，以及(Ii)肿瘤分泌的外切体可以将乙酰肝素酶运送到 并增强其对化疗的抵抗力。我们对目标1的工作假设是乙酰肝素酶 宿主细胞在肿瘤微环境中产生的物质支持和加速肿瘤生长， 转移和化疗耐药。这将在胰腺癌和骨髓瘤中进行研究。 表达不同水平宿主乙酰肝素酶的小鼠(转基因和基因敲除小鼠)。我们将调查 涉及的宿主细胞类型(如巨噬细胞、间质细胞)、它们对肿瘤进展的影响以及 抗药性和乙酰肝素酶抑制剂阻断宿主乙酰肝素酶这些作用的能力。我们的 Aim 2的工作假说是，乙酰肝素酶以货物形式存在于外切体中，被传递给受体肿瘤。 并增强它们的抗药性。我们将从机械上确定外切体是如何驱动的 化疗耐药及抗乙酰肝素酶治疗抑制外切体介导的可能性 化疗耐药。此外，AIM 3的工作将开发新的、高度特异的抗乙酰肝素酶单抗 抗体作为抗癌治疗药物。拟议的工作具有重大意义和创新性，因为它结合了 发现新的肝素酶作用机制，以最大限度地提高抗肝素酶的治疗效果 并改善患者的预后。

The long-term goal of our work is to understand how heparanase promotes the aggressive behavior of tumors and to use that knowledge to develop curative cancer therapies. We have identified multiple mechanisms through which heparanase drives cancer progression, metastasis and chemoresistance and established heparanase as a viable target for cancer therapy. Moreover, we catalyzed collaborative efforts aimed at developing and testing novel anti-heparanase drugs and demonstrated their efficacy in pre-clinical models of cancer leading to a currently ongoing clinical trial. The challenge now is to maximize anti-heparanase therapy to enhance its anti-tumor effects; a goal that will be attained through a thorough understanding of heparanase mechanisms of action. The overarching hypothesis guiding our work is that heparanase is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of many cancer patients and a prime target for therapy. This hypothesis is supported by studies focused predominantly on the impact of heparanase expressed by tumor cells. Our latest discoveries have revealed two novel, previously unexplored mechanisms related to heparanase regulation of cancer. We found that: (i) heparanase expressed by non-tumor (host) cells within the microenvironment can substantially contribute to tumor progression, and (ii) tumor secreted exosomes can shuttle heparanase to recipient cells and enhance their chemoresistance. Our working hypothesis for Aim 1 is that heparanase produced by host cells acts within the tumor microenvironment to support and accelerate tumor growth, metastasis and chemoresistance. This will be studied in pancreatic carcinoma and myeloma tumors growing in mice that express different levels of host heparanase (transgenic and knockout mice). We will investigate the type of host cells involved (e.g., macrophages, stromal cells), their impact on tumor progression and chemoresistance and the ability of heparanase inhibitors to block those effects of host heparanase. Our working hypothesis for Aim 2 is that heparanase present as cargo in exosomes is delivered to recipient tumor cells and enhances their chemoresistance. We will determine mechanistically how exosomes drive chemoresistance and investigate the potential of anti-heparanase therapy for inhibiting exosome-mediated chemoresistance. In addition, work in Aim 3 will develop new, highly specific anti-heparanase monoclonal antibodies as anti-cancer therapeutics. The proposed work is significant and innovative because it couples the discovery of new heparanase mechanisms of action with the objective of maximizing anti-heparanase therapy and improving patient outcome.