Heparanase regulation of tumor host interactions in myeloma and breast cancer

描述（由申请人提供）：我们工作的长期目标是确定硫酸肝素/肝素酶轴如何调节肿瘤行为，并利用这些知识开发新的癌症治疗方法。我们已经证明，硫酸肝素蛋白多糖syndecan-1和肝素酶协同作用，调节肿瘤微环境，从而促进骨髓瘤和乳腺癌的侵袭性肿瘤表型-两种毁灭性的癌症，家园和降解骨。我们现在的目标是确定肿瘤中肝素酶活性的机制，并利用新药靶向肝素酶进行治疗。尽管该领域的研究表明，肝素酶的功能是降解细胞外基质，从而促进肿瘤转移，但基于我们的新发现，我们假设肝素酶的表达和活性启动了广泛的下游效应，显著改变肿瘤微环境，刺激骨归巢肿瘤的生长、血管生成、转移和骨溶解。来自体内模型的数据表明，这些事件主要通过肝素酶介导的syndecan-1脱落上调、MMP-9表达增强和激活骨破坏发生。以下具体目的将明确肝素酶在骨髓瘤和乳腺癌中的功能和作用机制，并测试新的抗肝素酶药物，以根除这些癌症。Aim 1将确定肝素酶、syndecan-1和MMP-9之间的功能联系；目的2将确定肝素酶如何促进骨溶解；目的3将测试一类新的基于肝素的肝素酶抑制剂对乳腺癌的抗肿瘤疗效和作用机制。这些研究将利用成熟的体外和体内模型，包括SCID-hu模型，其中人类肿瘤细胞在人骨内生长。这项工作将对肝素酶的功能和作用机制产生新的见解，并为推动新的肝素酶抑制剂进入临床试验提供必要的临床前数据。公共卫生相关性：肝素酶是一种由癌细胞产生的蛋白质，在帮助癌细胞在全身生长和扩散方面起着重要作用。该项目旨在对肝素酶在多发性骨髓瘤和乳腺癌中的作用机制提供新的认识，并测试新的抗肝素酶药物来阻止癌症的生长。

DESCRIPTION (provided by applicant): The long-term objective of our work is to determine how the heparan sulfate/heparanase axis regulates tumor behavior and to use this knowledge to develop new therapies for cancer. We have demonstrated that the heparan sulfate proteoglycan syndecan-1 and heparanase work synergistically to condition the tumor microenvironment thereby promoting an aggressive tumor phenotype in myeloma and breast cancer - two devastating cancers that home to and degrade bone. Our goal now is to determine the mechanism of heparanase activity in tumors and to target heparanase therapeutically using novel drugs. Although work in the field suggests that heparanase functions to degrade extracellular matrix and thereby promote tumor metastasis, based on our new discoveries we hypothesize that heparanase expression and activity initiates broad downstream effects that dramatically alter the tumor microenvironment to stimulate growth, angiogenesis, metastasis and osteolysis of bone-homing tumors. Data from in vivo models indicates that these events occur largely via heparanase-mediated upregulation of syndecan-1 shedding, enhanced MMP-9 expression and activated destruction of bone. The following specific aims will define the function and mechanism of action of heparanase in myeloma and breast cancer and test novel anti-heparanase drugs with the aim of eradicating these cancers. Aim 1 will determine the functional link between heparanase, syndecan-1 and MMP-9; Aim 2 will determine how heparanase enhances osteolysis; Aim 3 will test the anti-tumor efficacy and mechanism of action of a new class of heparin-based inhibitors of heparanase against breast cancer. These studies will utilize well-developed in vitro and in vivo models including the SCID-hu model in which human tumor cells are grown within human bone. This work will generate novel insight into heparanase function and mechanism of action and provide pre-clinical data necessary to drive new heparanase inhibitors toward clinical trials. PUBLIC HEALTH RELEVANCE: Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to provide a new understanding about how heparanase works in multiple myeloma and breast cancer and to test new anti-heparanase drugs to block cancer growth.