Heparanase in Tumor Progression, Metastasis and Chemoresistance

我们工作的长期目标是了解乙酰肝素酶如何促进 肿瘤的侵袭性行为，并利用这些知识来开发治愈性癌症疗法。我们有 确定了乙酰肝素酶驱动癌症进展、转移和转移的多种机制， 化疗耐药性，并建立了乙酰肝素酶作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，并证明了其 在癌症的临床前模型中的有效性导致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作用;这一目标将通过 深入了解乙酰肝素酶的作用机制。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因子， 许多癌症患者的不良结果和治疗的主要目标。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。我们最新 这些发现揭示了两种新的、以前未探索的与乙酰肝素酶调节有关的机制， 癌我们发现：（i）由微环境中的非肿瘤（宿主）细胞表达的乙酰肝素酶可以 肿瘤分泌的外泌体可以将乙酰肝素酶穿梭至 受体细胞并增强其化学抗性。我们对Aim 1的工作假设是乙酰肝素酶 在肿瘤微环境中起作用以支持和加速肿瘤生长， 转移和化学抗性。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（转基因和敲除小鼠）。我们将调查 涉及的宿主细胞的类型（例如，巨噬细胞，基质细胞），它们对肿瘤进展的影响， 化学抗性和乙酰肝素酶抑制剂阻断宿主乙酰肝素酶的那些作用的能力。我们 目标2的工作假设是作为外泌体中的货物存在的乙酰肝素酶被递送至受体肿瘤 细胞并增强其化学抗性。我们将从机制上确定外泌体如何驱动 化疗耐药性，并研究抗乙酰肝素酶治疗抑制外泌体介导的 化学抗性此外，Aim 3的工作将开发新的、高度特异性的抗乙酰肝素酶单克隆抗体。 抗体作为抗癌治疗剂。拟议的工作是重要的和创新的，因为它耦合的 发现新的乙酰肝素酶作用机制，目的是使抗乙酰肝素酶治疗最大化 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.