OVARIAN CANCER OR PRIMARY PERITONEAL CARCINOMA

卵巢癌或原发性腹膜癌

• 批准号: 7378874
• 负责人: DEBORAH K ARMSTRONG
• 金额: $ 0.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378874
• 关键词: OVARIAN; CANCER; PRIMARY; PERITONEAL; CARCINOMA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is accumulating evidence that angiogenesis plays a central role in ovarian cancer (7,8,), but the impact of angiogenic activity on clinical outcomes for patients with ovarian cancer has yet to be convincingly determined. However, several historical cohort studies have suggested a negative prognostic relationship (4, 9-11). For example, Gasparini et al. recently reported on 60 women with advanced (FIGO stage III and IV) ovarian carcinoma treated with standard surgery and chemotherapy, in which MVD was determined by quantitative immunohistochemistry (IHC) for the expression of CD31, an endothelial antigen. They demonstrated that CD31 expression was a negative prognostic factor for survival.(4) The same association was demonstrated by Hollingsworth et al. in their study of CD31 expression by quantitative IHC in 43 similar patients. (9) Mean MVD was independently prognostic for poor survival by multivariate analysis. In addition tousing immunohistochemistry (IHC) to identifyspecific proteins known to participate in angiogenesis, intratumoral angiogenesis may be evaluated through analysis of tumor micro-vessel density (MVD) determined by IHC using antibodies to CD31 CD105, and VCAM-I. CD-MRI studies have also been used to examine the relationship between CD-MRI-derived characteristics and both tumor MVD and VEGF expression, from cancers of the uterine cervix.(12-16) Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21), calculated from CD-MRI were directly associated with MVD in primary tumors treated by radical hysterectomy. However, no significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. Interestingly, k21 was shown to be a significant predictor of poor patient survival.(12,13,16) It should be noted that a small DTPA (0.5 kD) was used in these studies. Given that a direct relationship has been demonstrated between the expression of biomarkers of angiogenesis and the biologic behavior of EOC, it would seem implicit that pharmacological inhibitors of angiogenesis could arrest tumor progression.(17- 20) Indeed, active inhibitors of tumor angiogenesis have been identified based on in vitro and pre-clinical cytostatic activity.(21-31) Neutralizing anti-VEGF monoclonal antibodies have demonstrated therapeutic activity in a variety of preclinical solid tumor models.(32,33) Bevacizumab is a recombinant humanized version of a murine anti-human VEGF monoclonal antibody, named rhuMAb VEGF. Bevacizumab has been advanced into clinical development by Genentech, Inc. for use as a single agent to induce tumor growth inhibition in patients with solid tumors and for use in combination with cytotoxic chemotherapy to delay the time to disease progression in patients with metastatic solid tumors. Inhibition of VEGF using this anti-VEGF monoclonal antibody blocks the growth of a number of human cancer cell lines in nude mice by interfering with endothelial cell proliferation and neovascularization required for the continued growth of tumors.(34) This pathway seems to be important in ovarian cancer progression and metastasis. Both preclinical and clinical studies have been completed to evaluate the safety, maximally tolerated dose (MTD) and pharmacokinetics of Bevacizumab.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。越来越多的证据表明血管生成在卵巢癌中起着重要作用（7，8，），但血管生成活性对卵巢癌患者临床结局的影响尚未令人信服地确定。然而，几项历史队列研究表明，预后呈负相关（4，9-11）。例如，Gasparini等最近报道了60例晚期（FIGO III期和IV期）卵巢癌患者接受标准手术和化疗，其中MVD通过定量免疫组织化学（IHC）测定CD 31（一种内皮抗原）的表达。他们证明了CD 31表达是生存的负性预后因素。(4)Hollingsworth等人在43例类似患者中通过定量IHC进行的CD 31表达研究中证实了相同的相关性。(9)多因素分析显示平均MVD是预后不良的独立预后因素。除了使用免疫组织化学（IHC）来鉴定已知参与血管生成的特异性蛋白质外，还可以通过使用针对CD 31、CD 105和VCAM-1的抗体通过IHC测定的肿瘤微血管密度（MVD）分析来评估肿瘤内血管生成。CD-MRI研究也被用于检查CD-MRI衍生特征与宫颈癌肿瘤MVD和VEGF表达之间的关系。（12-16）在根治性子宫切除术治疗的原发性肿瘤中，根据CD-MRI计算的药代动力学参数（振幅，A;交换速率常数，k21）与MVD直接相关。然而，没有发现药代动力学参数（A，k21）和VEGF表达之间的显着关联。有趣的是，k21被证明是患者生存率差的重要预测因子。(12，13，16）应注意，在这些研究中使用了小DTPA（0.5 kD）。鉴于已经证明血管生成生物标志物的表达与EOC的生物学行为之间存在直接关系，似乎暗示血管生成的药理学抑制剂可以阻止肿瘤进展。(17-20）事实上，肿瘤血管生成的活性抑制剂已经基于体外和临床前细胞生长抑制活性被鉴定。（21-31）中和性抗VEGF单克隆抗体已在多种临床前实体瘤模型中显示出治疗活性。(32贝伐单抗是鼠抗人VEGF单克隆抗体的重组人源化版本，称为rhuMAb VEGF。贝伐珠单抗已由Genentech，Inc.进入临床开发阶段。用作单一药剂以诱导实体瘤患者的肿瘤生长抑制，以及与细胞毒性化疗联合使用以延迟转移性实体瘤患者的疾病进展时间。使用这种抗VEGF单克隆抗体抑制VEGF通过干扰肿瘤持续生长所需的内皮细胞增殖和新血管形成来阻断裸鼠中许多人癌细胞系的生长。(34)该通路似乎在卵巢癌进展和转移中很重要。临床前和临床研究均已完成，以评估贝伐珠单抗的安全性、最大耐受剂量（MTD）和药代动力学。