Protease activated receptor-2 (PAR-2) signaling and metastatic ovarian cancer

蛋白酶激活受体 2 (PAR-2) 信号传导与转移性卵巢癌

• 批准号: 10204893
• 负责人: Toni M Antalis
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204893
• 关键词: Address; Agonist; Angiopoietins; Ascites; Biological Assay; Biological Markers; Biological Process; Blocking Antibodies; Cancer Etiology; Cancer Patient; Cell Line; Cell surface; Chemoresistance; Cleaved cell; Clinical; Clinical Trials; Coupled; Data; Diagnosis; Disease; Dose; Female; GTP-Binding Proteins; Goals; Human; In Vitro; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mediating; Membrane; Metastatic Malignant Neoplasm to the Ovary; Molecular; Neoplasm Metastasis; Outcome; PAR-2 Receptor; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Positioning Attribute; Process; Publishing; Recurrence; Research; Resistance; SKOV3 cells; Serine Protease; Signal Pathway; Signal Transduction; Survival Rate; Testing; Therapeutic; Time; Treatment Efficacy; Treatment-related toxicity; Tumor Angiogenesis; Tumor Burden; Tumor Cell Line; Variant; Vascular Endothelial Growth Factors; Woman; Xenograft Model; angiogenesis; antiangiogenesis therapy; clinical efficacy; conventional therapy; desensitization; experimental study; improved; in vivo; intraperitoneal; malignant breast neoplasm; mouse model; neoplastic cell; novel; ovarian neoplasm; patient response; pre-clinical; side effect; success; targeted treatment; testisin; therapeutic target; tumor

SUMMARY Ovarian cancer is the most lethal gynecological malignancy. One in 69 women will develop ovarian cancer, and less than half will survive for five years. Despite a number of recent advances in our understanding of ovarian cancer etiology and pathobiology, the survival rate of patients diagnosed with ovarian cancer is low when compared to that of breast or prostate cancer. Factors contributing to this poor survival rate are tumor persistence, tumor recurrence and chemoresistance. There is an urgent need to develop second line therapies to both improve the therapeutic efficacy of conventional treatments and to provide alternative therapeutic options for patients with recurrent ovarian cancer. Anti-angiogenesis therapies targeting the VEGF and the angiopoietins/Tie2 pathways have shown clinical efficacy and are currently being actively pursued as adjunct therapies for recurrent ovarian cancers. Unfortunately, outcomes of recent clinical trials have been mixed and non-responsiveness or resistance to anti-angiogenic treatment, toxicities and subsequent tumor recurrence and metastasis have limited therapeutic success. This is largely due to an incomplete of understanding of the basic mechanisms involved. The scientific premise underlying this research is that differential triggering of the G-protein coupled Protease Activated Receptor-2 (PAR-2) by different proteases modulates tumor angiogenesis important for ovarian tumor metastasis. We discovered the membrane-anchored serine protease, testisin (also known as PRSS21), to be aberrantly expressed in a broad range of ovarian cancers and to be a potent cell surface proteolytic activator of PAR-2. Strong preliminary data show that the aberrent constitutive expression of testisin in ovarian tumors promotes anti-angiogenic signaling and suppresses ovarian tumor metastasis and ascites formation in a preclinical xenograft model of ovarian cancer. This unique activity is unexpected, and reveals a major gap in our understanding of how PAR-2 angiogenic signals are modulated by different proteases, specifically those in spatial proximity to PAR-2. Such `biased agonism' may start to explain significant variations in patient responses to anti-angiogenic therapies in ovarian cancer patients. The proposed research plan will utilize primary human ovarian tumor cells and cell lines in concert with in vivo mouse models to address the following specific aims: 1) to determine mechanisms by which testisin suppresses experimental ovarian tumor metastasis, and 2) to determine molecular and cellular mechanisms associated with testisin-mediated desensitization PAR-2 and modulation of angiogenesis. Augmentation of the natural antagonism resulting from the testisin-PAR-2 pathway could find utility in combination with other anti-angiogenic therapies, to reduce therapeutic doses required, thereby minimizing side effects and provide a unique therapy for managing this devastating disease. The fact that females do not have a normal abundance of testisin makes testisin a unique and particularly attractive therapeutic target for ovarian tumors and also a potentially useful biomarker.

概括 卵巢癌是最致命的妇科恶性肿瘤。 69名女性将患上卵巢癌， 不到一半将存活五年。尽管我们对我们的理解有了许多最近的进步 卵巢癌的病因和病理学，诊断为卵巢癌的患者的存活率很低 与乳腺癌或前列腺癌相比。导致这种生存率较差的因素是肿瘤 持久性，肿瘤复发和化学抗性。迫切需要开发二线疗法 既提高常规治疗的治疗功效，并提供替代性治疗 复发性卵巢癌患者的选择。针对VEGF和的抗血管生成疗法 血管生成素/TIE2途径已显示出临床功效，目前正在积极追求辅助 复发性卵巢癌的疗法。不幸的是，最近的临床试验结果混合在一起， 对抗血管生成治疗，毒性和随后的肿瘤复发无反应或抵抗力 转移的治疗成功有限。这主要是由于对 涉及的基本机制。这项研究的科学前提是，差异触发 不同蛋白酶调节肿瘤的G蛋白偶联蛋白酶活化受体-2（PAR-2）调节 血管生成对卵巢肿瘤转移很重要。我们发现了膜锚定的丝氨酸 蛋白酶，睾丸（也称为PRSS21），在广泛的卵巢癌和 成为PAR-2的有效细胞表面蛋白水解活化剂。强大的初步数据表明异常 卵巢肿瘤中睾丸的本构表达促进抗血管生成信号传导并抑制 在卵巢癌的临床前异种移植模型中，卵巢肿瘤转移和腹水形成。这 独特的活动是出乎意料的，并揭示了我们对PAR-2血管生成的理解的主要差距 信号由不同的蛋白酶进行调节，特别是在空间接近PAR-2的蛋白酶。如此偏见 激动剂可能开始解释患者对抗血管生成疗法的反应显着差异 卵巢癌患者。拟议的研究计划将利用原发性人类卵巢肿瘤细胞和细胞 与体内鼠标模型一致的行，以解决以下特定目的：1）确定 睾丸抑制实验性卵巢肿瘤转移的机制，2）确定 与睾丸介导的脱敏PAR-2和调节有关的分子和细胞机制 血管生成。睾丸蛋白-PAR-2途径引起的自然拮抗作用的增强可能 找到与其他抗血管生成疗法结合使用的实用程序，以减少所需的治疗剂量 最大程度地减少副作用，并提供一种独特的疗法来管理这种毁灭性疾病。事实 雌性没有正常的睾丸使睾丸成为独特，特别有吸引力的睾丸 卵巢肿瘤的治疗靶标，也是潜在有用的生物标志物。