肿瘤抗原OVA66对化疗敏感性的调控作用及其在卵巢癌个体化治疗中的应用价值

Personalized treatment/therapy for cancer patients represents the future of clinical oncology. It has been impressing needed to discover and validate biomarkers for predicting chemosensitivity and/or side effect for ovarian cancers. OVA66 (ovarian cancer-associated antigen 66), a novel member of cancer-testis antigen family, which was identified by using serological analysis of recombinant cDNA expression libraries (SEREX) method in Chinese ovarian carcinoma. Previously findings indicated that OVA66 might have great potential for prevention, diagnosis and treatment of malignancies. In this project, we are going to explore continuously and intensively in the following aspects: 1) the expression and clinical significance of OVA66 in ovarian cancer, especially the relationship between OVA66 level and disease stage, pathological type, effect of chemotherapy and prognosis of ovarian cancer patients; 2) level of serum OVA66 antibody in ovarian cancer patients and its sensitivity/specificity for predicting treatment response of platinum-based chemotherapy; 3) to investigate the effect of OVA66 level on sensitivity of cancer cells to common chemotherapeutic agents, and to elucidate the underlying mechanisms of the regulatory role of OVA66 by focusing survival signals and apoptosis related participants. Through the above work, the clinical potential of OVA66 as a biomarker for personalized treatment of ovarian cancer will be confirmed generally, which could provide new insights in personalized cancer medicine and might have a promising perspective of clinical application.

个体化治疗是临床肿瘤学的重要发展方向，目前迫切需要寻找并鉴定预测卵巢癌化疗敏感性和/或毒副作用相关的标志物。OVA66是应用重组cDNA文库血清学分析（SEREX），从中国人卵巢癌中发现的一个新的肿瘤/睾丸抗原。前期的研究工作提示OVA66在肿瘤防诊治中具有潜在价值。本项目主要从三方面不断探索和深入研究：1）OVA66在卵巢癌中的表达及其临床意义，着重分析组织OVA66表达水平与卵巢癌分期、病理类型、化疗效果和预后等的关系；2）卵巢癌患者血清OVA66抗体的含量及其预测卵巢癌铂类化疗反应的敏感性和特异性；3）运用体内和体外模型，分析OVA66表达水平对临床常用化疗药物敏感性的影响，并以细胞存活信号和凋亡相关分子为切入点，探讨OVA66调控作用的分子机制。通过上述工作，明确OVA66作为分子标记在指导卵巢癌个体化治疗中的价值，具有重要的理论意义和良好的应用前景；有可能成为这一领域新的突破点。

OVA66/CML66/Nudcd1是应用重组cDNA文库血清学分析（SEREX），从中国人卵巢癌中发现的一个新的肿瘤/睾丸抗原。本项目研究结果表明OVA66表达水平与卵巢癌临床分期、病理分级密切相关：低分期的组织中OVA66相对低表达或不表达，而在高分期的组织中高表达，正常和癌旁组织中基本不表达；组织高表达OVA66的卵巢癌患者长期生存率明显低于低表达的患者。另一方面，肿瘤抗原OVA66具有类似癌基因的功能，可以促进细胞存活，增强肿瘤细胞对化疗药物的抵抗性，可能通过调节卵巢癌细胞 PI3K/Akt信号途径，影响抗凋亡蛋白Bcl-2、Bcl-xL，促凋亡蛋白Bax以及抑癌基因P53的表达，促进VEGF的分泌等发挥对细胞存活及化疗药物敏感性调控作用存活；并可能与HSP47相互作用参与肿瘤的发生、发展。进一步深入研究OVA66生物学功能及分子机制，不仅具有重要理论价值，而且有望为提高临床肿瘤的诊治水平提供新的思路。