Glycosaminoglycan-based inhibitors for treatment of prostate cancer

用于治疗前列腺癌的糖胺聚糖抑制剂

基本信息

批准号：
7265404
负责人：
Vinata B Lokeshwar
金额：
$ 26.05万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7265404
关键词：
7-hydroxycoumarin Anchorage-Independent Growth Androgen Receptor Androgens Apoptosis Appendix B-Lymphocytes Bioavailable Blood Circulation Cancer Model Cell Cycle Arrest Cells Characteristics Class Complementary DNA DU145 Dose Endoglycosidases Enzymes Event Focal Adhesion Kinase 1 G2/M Arrest Glycosaminoglycans Growth Health Histologic Hyaluronic Acid Hyaluronidase Immunohistochemistry Implant In Vitro Induction of Apoptosis Infiltration Inorganic Sulfates LNCaP Laboratories Lead Liver Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Molecular Neoplasm Metastasis Nude Mice Oligonucleotides Oligosaccharides Oral Oral Administration PSA level Patients Polymers Property SPAM1 gene Signal Transduction Specimen Staging Staining method Stains System Testing Therapeutic Therapeutic Agents Tissues Toxic effect Transfection Transgenic Model Transgenic Organisms Tumor-Derived Umbelliferones Unspecified or Sulfate Ion Sulfates Vascularization Xenograft Model Xenograft procedure angiogenesis antitumor drug base cancer cell caspase-8 cell growth cell motility dietary supplements follow-up improved in vivo inhibitor/antagonist neoplastic cell novel novel therapeutics prognostic tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to target the tumor-associated hyaluronic acid-hyaluronidase (HA-HAase) system to develop novel therapeutics for prostate cancer (CaP). HA is a glycosaminoglycan that promotes tumor growth and metastasis and HAase is an endoglycosidase that degrades HA into angiogenic fragments. HYAL1 is a tumor-derived HAase, secreted by CaP cells. Combined HA-HYAL1 expression in CaP tissues is an independent prognostic indicator for predicting CaP progression. Blocking HYAL1 expression in CaP cells, by antisense cDNA transfection, decreases tumor growth, invasion and vascularization in xenografts. Sulfated HA (sHA) polymer and small sHA oligosaccharides are potent inhibitors of HYAL1 activity which inhibit CaP cell growth by causing cell-cycle arrest and inhibit the growth of CaP xenografts. These agents decrease activation of focal adhesion kinase and down regulate androgen receptor levels and activity. 4-methyl-umbelliferone (4-MU), used as a dietary supplement for the treatment of liver aliments, inhibits HA synthesis. By blocking pericellular HA formation, 4-MU induces apoptosis in CaP cells by caspase-8 activation and inhibits the growth of CaP xenografts. Both sHA and 4-MU are orally bioavailable, active against both androgen dependent and independent CaP cells and show no histologic or systemic toxicity upon long-term treatment. The main hypothesis to be tested in the proposed project is that, sHA and 4-MU, either alone or in combination, will abrogate CaP growth and its progression. The efficacy of sHA compounds to inhibit cell growth and invasion will be evaluated in vitro. Inhibition of tumor growth, metastasis and angiogenesis will be examined in 3 CaP xenograft models (i.e., orthotopic tumor implant, induced metastasis and intra-osseous growth models). Effect of sHA on HA-HYAL1 mediated intracellular signaling will also be investigated (Aim 1). Effect of 4-MU in controlling CaP cell growth, invasion and motility will be investigated in vitro. Inhibition of tumor growth and metastasis by 4-MU, either alone or in combination with sHA, will be examined in the three CaP xenograft models, as described above. Mechanism of 4-MU induced apoptosis and abrogation of HA- mediated intracellular signaling will also be investigated (Aim 2). Efficacy of sHA and 4-MU, either alone or in combination, as stage-specific treatments for CaP growth and metastasis will be investigated in two transgenic models of CaP (Aim 3). Relevance: This is the first study that proposes to evaluate inhibitors of the HA-HYAL1 system as therapeutic agents for the treatment of CaP. If proven efficacious, sHA compounds and 4-MU will be a novel class of glycosaminoglycan-based target-specific anti-tumor drugs.

描述（由申请人提供）：该提案的总体目标是针对肿瘤相关透明质酸-透明质酸酶（HA-HAase）系统来开发前列腺癌（CaP）的新疗法。 HA 是一种糖胺聚糖，可促进肿瘤生长和转移，HAase 是一种糖苷内切酶，可将 HA 降解为血管生成片段。 HYAL1 是一种肿瘤来源的 HAase，由 CaP 细胞分泌。 CaP 组织中 HA-HYAL1 的联合表达是预测 CaP 进展的独立预后指标。通过反义 cDNA 转染阻断 CaP 细胞中 HYAL1 的表达，可减少异种移植物中的肿瘤生长、侵袭和血管化。硫酸化 HA (sHA) 聚合物和小 sHA 寡糖是 HYAL1 活性的有效抑制剂，可通过引起细胞周期停滞来抑制 CaP 细胞生长，并抑制 CaP 异种移植物的生长。这些药物可减少粘着斑激酶的激活并下调雄激素受体水平和活性。 4-甲基-伞形酮 (4-MU) 用作治疗肝脏食物的膳食补充剂，可抑制 HA 合成。通过阻断细胞周 HA 形成，4-MU 通过 caspase-8 激活诱导 CaP 细胞凋亡，并抑制 CaP 异种移植物的生长。 sHA 和 4-MU 均具有口服生物利用度，对雄激素依赖性和非依赖性 CaP 细胞均具有活性，并且在长期治疗后没有显示出组织学或全身毒性。该项目要测试的主要假设是，sHA 和 4-MU，无论是单独使用还是组合使用，都会消除 CaP 的生长及其进展。 sHA 化合物抑制细胞生长和侵袭的功效将在体外进行评估。将在 3 个 CaP 异种移植模型（即原位肿瘤植入、诱导转移和骨内生长模型）中检查对肿瘤生长、转移和血管生成的抑制。还将研究 sHA 对 HA-HYAL1 介导的细胞内信号传导的影响（目标 1）。将在体外研究 4-MU 在控制 CaP 细胞生长、侵袭和运动中的作用。如上所述，将在三种 CaP 异种移植模型中检查 4-MU 单独或与 sHA 组合对肿瘤生长和转移的抑制作用。还将研究 4-MU 诱导细胞凋亡和消除 HA 介导的细胞内信号传导的机制（目标 2）。将在两种 CaP 转基因模型中研究 sHA 和 4-MU 单独或组合作为 CaP 生长和转移阶段特异性治疗的功效（目标 3）。相关性：这是第一项建议评估 HA-HYAL1 系统抑制剂作为治疗 CaP 的药物的研究。如果被证明有效，sHA 化合物和 4-MU 将成为一类新型的基于糖胺聚糖的靶向特异性抗肿瘤药物。