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Heparanase in Tumor Progression, Metastasis and Chemoresistance

乙酰肝素酶在肿瘤进展、转移和化疗耐药中的作用

基本信息

批准号：
10171563
负责人：
Ralph D Sanderson
金额：
$ 34.2万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171563
关键词：
Aggressive behavior Animal Model Automobile Driving Biological Models Cancer Model Cancer Patient Cancer cell line Cells Chemicals Chemoresistance Clinic Clinical Trials Couples Development Docking Exhibits Exposure to Goals Growth Heparanase inhibitors Heparin In Vitro Investigation Knockout Mice Knowledge Malignant Neoplasms Mediating Mediator of activation protein Monoclonal Antibodies Multiple Myeloma Mus Neoplasm Metastasis Outcome Pancreatic carcinoma Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Play Pre-Clinical Model Primary Neoplasm Probability Proteins Regulation Resistance Resources Role Specificity Stromal Cells Testing Therapeutic Transgenic Mice Tumor Biology Tumor-Derived Work anti-cancer therapeutic antitumor effect cancer cell cancer therapy chemotherapy design exosome experience heparanase improved in vivo innovation macrophage neoplastic cell novel pancreatic cancer cells pre-clinical success targeted cancer therapy targeted treatment tool tumor tumor behavior tumor growth tumor initiation tumor microenvironment tumor progression

项目摘要

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.

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行为并利用这些知识来开发治疗性癌症疗法。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学耐药性并将乙酰肝素酶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证明了其效果在癌症临床前模型中的功效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；将通过以下方式实现的目标彻底了解乙酰肝素酶的作用机制。指导我们工作的总体假设是乙酰肝素酶是癌症侵袭性表型的主要调节因子，是癌症侵袭性表型的重要贡献者许多癌症患者的不良预后和治疗的主要目标。这个假设得到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。我们最新的研究发现揭示了两种与乙酰肝素酶调节相关的先前未探索的新颖机制癌症。我们发现：（i）微环境中的非肿瘤（宿主）细胞表达的乙酰肝素酶可以显着促进肿瘤进展，并且（ii）肿瘤分泌的外泌体可以将乙酰肝素酶运送到受体细胞并增强其化疗耐药性。我们对目标 1 的工作假设是乙酰肝素酶由宿主细胞产生，在肿瘤微环境中发挥作用，支持和加速肿瘤生长，转移和化疗耐药性。这将在胰腺癌和骨髓瘤肿瘤中进行研究表达不同水平宿主乙酰肝素酶的小鼠（转基因小鼠和基因敲除小鼠）。我们将调查所涉及的宿主细胞类型（例如巨噬细胞、基质细胞）、它们对肿瘤进展的影响以及化疗耐药性以及乙酰肝素酶抑制剂阻断宿主乙酰肝素酶的作用的能力。我们的目标 2 的工作假设是外泌体中作为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疗耐药性。我们将从机械上确定外泌体如何驱动化学耐药性并研究抗乙酰肝素酶治疗抑制外泌体介导的潜力化学耐药性。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疗法。拟议的工作具有重要意义和创新性，因为它将发现新的乙酰肝素酶作用机制，目的是最大化抗乙酰肝素酶治疗并改善患者的治疗效果。