Targeting MUC16 transactivation for ovarian cancer treatment

摘要 尽管取得了现代进展，卵巢癌仍然是与癌症相关的死亡的最常见原因之一。 美国的女性。由于缺乏有效的筛查测试，卵巢癌通常出现在晚期。 舞台。目前卵巢癌的治疗主要局限于手术和化疗，五年 存活率低于50%。迫切需要新的治疗方法来帮助患有这种致命疾病的患者 疾病。卵巢癌的一个独特特征是80%以上的患者血清CA-1水平较高。 125.生物信息学分析表明，CA-125mRNA在妇科癌细胞中也高表达， 在卵巢癌细胞中最高，但在大多数其他癌细胞或正常细胞中不是。CA-125已经被 被认为是治疗卵巢癌的理想和独特的靶点；然而，靶向CA-125蛋白用于 卵巢癌的治疗从来没有成功过。 MUC16(编码CA-125的基因)在卵巢癌细胞中的特异性转录激活尚不清楚， 针对特定的MUC16反式激活用于卵巢癌治疗的尝试从未尝试过。 然而，我们的总体目标是确定靶向MUC16基因特异性的可行性 通过开发一种只能在卵巢中复制的条件复制型腺病毒(CRAd)来实现反式激活 表达CA-125的癌细胞以及检测感染病毒的癌细胞诱导保护性抗肿瘤细胞的能力 可用于卵巢癌治疗的癌症免疫反应。 我们假设，使用带有MUC16反式激活序列的CRAd来控制 病毒复制是针对卵巢特异性MUC16基因反式激活的一种创新和实用的方法 癌症治疗。我们有令人信服的初步数据来支持我们的假设。我们期望实现我们的目标 通过追求以下具体目标实现总体目标： 目的1：开发能在表达CA-125的卵巢癌细胞中特异性复制的有效CRAD。 目的：评价CRAds对免疫缺陷和免疫活性小鼠的抗癌活性。 目的3：选择一种有效的CRAd并评估其对原代卵巢癌细胞的溶瘤活性 从病人那里。 我们预计，构建依赖于MUC16反式激活进行复制的CRAd的策略将 对于卵巢癌的治疗是可行和有效的。成功完成拟议的研究将产生 一种有效的靶向制剂，不仅能特异性地在卵巢癌细胞中复制和裂解，还能激活 一种保护性抗癌免疫反应。更好地定义MUC16转录元件也将为 为更详细的卵巢癌CA-125调控机制研究奠定基础，这可能 揭示卵巢癌治疗的新靶点。

ABSTRACT Despite modern advances, ovarian cancer remains one of the most common causes of cancer-related death of women in the US. Due to lack of an effective screening test, ovarian cancer typically presents at an advanced stage. Current treatment of ovarian cancer is primarily limited to surgery and chemotherapy, and the five-year survival rate is below 50%. New treatments are urgently needed to help patients suffering from this deadly disease. A unique feature of ovarian cancer is that more than 80% of patients express a high serum level of CA- 125. Bioinformatic analysis shows that CA-125 mRNA is also highly expressed in gynecological cancer cells, with the highest in ovarian cancer cells, but not in most other cancer cells or in normal cells. CA-125 has been regarded as an ideal and unique target for ovarian cancer treatment; however, targeting CA-125 protein for ovarian cancer treatment has never been successful. Specific transcriptional activation of MUC16 (the gene encoding CA-125) in ovarian cancer cells is poorly defined, and targeting specific MUC16 transactivation for ovarian cancer treatment has never been attempted. Nevertheless, our overall objective is to determine the feasibility of targeting the MUC16 gene specific transactivation by developing a conditionally replicative adenovirus (CRAd) that can only replicate in ovarian cancer cells expressing CA-125 and to gauge the ability of virus-infected cancer cells to induce a protective anti- cancer immune response that can be harnessed for ovarian cancer treatment. We hypothesize that using a CRAd with the MUC16 transactivation sequence to control an essential gene for virus replication is an innovative and practical way to target the specific MUC16 gene transactivation for ovarian cancer treatment. We have compelling preliminary data to support our hypothesis. We expect to accomplish our overall objective by pursuing the following Specific Aims: Aim 1: Develop potent CRAds that specifically replicate in ovarian cancer cells expressing CA-125. Aim 2: Evaluate the anti-cancer activity of CRAds in immunodeficient and immunocompetent mice. Aim 3: Select a potent CRAd and assess the oncolytic activity in primary ovarian cancer cells collected from patients. We anticipate that the strategy of constructing a CRAd dependent on MUC16 transactivation for replication will be feasible and effective for ovarian cancer treatment. Successful completion of the proposed studies will yield a potent targeted agent that not only specifically replicates in and lyses ovarian cancer cells, but also activates a protective anti-cancer immune response. Better definition of MUC16 transcriptional elements will also lay the groundwork for more detailed mechanistic investigations into CA-125 regulation in ovarian cancers, which may reveal new targets to explore for ovarian cancer treatment.