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.

摘要 卵巢癌是最致命的妇科恶性肿瘤。每69名女性中就有一人会患上卵巢癌， 而只有不到一半的人能存活五年。尽管我们最近在理解上取得了一些进展 卵巢癌的病因和病理生物学方面，确诊为卵巢癌的患者存活率较低 与乳腺癌或前列腺癌相比。导致这种低存活率的因素是肿瘤 持久性、肿瘤复发和化疗耐药。迫切需要发展二线疗法。 既要提高传统疗法的疗效，又要提供替代疗法 复发性卵巢癌患者的选择。以血管内皮生长因子和血管内皮生长因子为靶点的抗血管生成治疗 Angiopoietins/Tie2通路已显示出临床疗效，目前正积极作为辅助手段进行研究 复发性卵巢癌的治疗。不幸的是，最近的临床试验结果好坏参半。 抗血管生成治疗无反应或抵抗、毒性反应和随后的肿瘤复发 和转移都限制了治疗的成功。这在很大程度上是由于对 涉及的基本机制。这项研究背后的科学前提是，差异触发 G蛋白偶联蛋白酶激活受体-2(PAR-2)对肿瘤的调控作用 血管生成在卵巢肿瘤转移中的重要作用。我们发现了膜锚定的丝氨酸 蛋白酶，睾丸蛋白(也称为PRSS21)，在广泛的卵巢癌和 是一种有效的PAR-2细胞表面蛋白分解激活剂。强劲的初步数据显示，反常 卵巢肿瘤中睾丸素的组成性表达促进抗血管生成信号转导和抑制 卵巢癌临床前异种移植模型中的卵巢肿瘤转移和腹水形成。这 独特的活性是意想不到的，它揭示了我们对PAR-2血管生成机制的理解上的一个重大差距 信号受不同的蛋白水解酶的调节，特别是那些在空间上接近PAR-2的水解酶。如此“有偏见” 激动症可能开始解释患者对抗血管生成治疗的显著差异 卵巢癌患者。拟议的研究计划将利用原代人类卵巢肿瘤细胞和细胞 与活体小鼠模型相一致的线条，以解决以下具体目标：1)确定 睾丸素抑制实验性卵巢肿瘤转移的机制，以及2)确定 睾丸蛋白介导的PAR-2脱敏及其调控的分子和细胞机制 血管生成的影响。增强睾丸-PAR-2途径产生的自然拮抗作用可能 找到与其他抗血管生成疗法相结合的有效方法，从而减少所需的治疗剂量 将副作用降至最低，并为管理这种毁灭性的疾病提供了一种独特的疗法。事实是， 女性没有正常丰富的睾丸，这使得睾丸成为一种独特而特别吸引人的东西 卵巢肿瘤的治疗靶点，也是一个潜在的有用的生物标志物。