CUDC-101联合cisplatin对卵巢癌腹水细胞spheroid形成及转移机制的相关研究

Ovarian cancer is the most lethal malignancy of the female reproductive system, and is typically diagnosed in advanced stages. The unique pattern of metastasis of ovarian cancer through the circulation of peritoneal fluid, is enhanced by growth factors present in the ascites and omentum. Surgical tumor cytoreduction, followed by platinum-based chemotherapy is the standard treatment for advanced ovarian cancer. Although response rates in advanced disease are initially promising，most patients eventually relapse and become resistant to cisplatin. Once platinum resistance occurs, the prognosis is very poor and survival is limited. Tumorigenicity of ovarian cancer is related to the overexpression of histone deacetylase (HDAC), and the chemoresistance of ovarian cancer is associated with overexpression of EGFR/HER2 which is regulated by HDACs and HDAC inhibitors have shown promise in treating many solid tumors. We found that the combination of Trichostatin A, an HDAC inhibitor, in combination with low dose cisplatin significantly enhanced the response to cisplatin and suppressed tumorigeniciy of cisplatin resistant ovarian cancer cells in vitro and in vivo. Based on these findings, we will investigate the HDAC/EGFR/HER2 inhibitor, CUDC-101, to determine if this drug can resensitize platinum resistant ovarian cancer cells to cisplatin, and eventually provide a more promising treatment for platinum resistant ovarian cancer patients.

卵巢癌是目前恶性程度最高的女性生殖系统恶性肿瘤。卵巢癌主要通过腹腔液的循环来转移，而腹水中和网膜分泌的生长因子可以促进转移的发生。卵巢癌细胞减灭术后铂类药物化疗是目前晚期卵巢癌的主要治疗方法，尽管晚期肿瘤细胞初次对化疗药物敏感，但最终都将复发并对铂类药物产生耐药，预后通常较差且生存时间明显减少。卵巢癌的发生与组蛋白去乙酰化酶（HDAC）的高表达相关，而耐药问题又与EGFR/HER2的高表达有关，此外EGFR/HER2的表达又受到HDAC的调控，并且研究表明HDAC抑制剂对实性肿瘤有较好的效果。我们发现HDAC抑制剂Trichostatin A联合低剂量的cisplatin可以显著提高耐药肿瘤细胞对cisplatin的敏感性。因此，我们将探讨一种新型的HDAC/EGFR/HER2抑制剂CUDC-101能否使铂类耐药卵巢癌细胞对cisplatin再敏感，从而有效改善卵巢癌患者的预后。