Targeting MUC16 transactivation for ovarian cancer treatment

靶向 MUC16 反式激活治疗卵巢癌

• 批准号: 10357490
• 负责人: Edward Wenge Wang
• 金额: $ 20.57万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357490
• 关键词: 19p13.2; Bioinformatics; CA-125 Antigen; Cancer Etiology; Cancer Patient; Cancer cell line; Cessation of life; Chromosomes; Clinical; Cytotoxic agent; DNA; Data; Diagnosis; Disease; Elements; Essential Genes; Firefly Luciferases; Future; Genes; Genetic Transcription; Genomic DNA; Human; Immune response; Immunocompetent; Investigation; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Messenger RNA; Modernization; Mus; Normal Cell; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Patients; Phase I Clinical Trials; Pre-Clinical Model; Preparation; Process; Proteins; Radioisotopes; Regulation; Reporter; Reporting; Serum; Survival Rate; T cell therapy; Testing; Transactivation; Transcriptional Activation; Virus; Virus Replication; Woman; Xenograft procedure; anti-cancer; antibody conjugate; anticancer activity; cancer cell; cancer therapy; chemotherapy; chimeric antigen receptor; conditionally replicative adenovirus; immunodeficient mouse model; immunogenicity; innovation; malignant ascites; mouse model; phase I trial; randomized placebo controlled trial; screening; targeted agent; vector

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.

抽象的 尽管现代取得了进步，卵巢癌仍然是癌症相关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，卵巢癌通常已是晚期 阶段。目前卵巢癌的治疗主要限于手术和化疗，五年内 成活率低于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超过 80% 的患者血清中表达高水平的 CA- 125. 生物信息分析显示，CA-125 mRNA在妇科癌细胞中也高表达， 在卵巢癌细胞中含量最高，但在大多数其他癌细胞或正常细胞中含量较低。 CA-125 已 被视为卵巢癌治疗的理想且独特的靶点；然而，针对 CA-125 蛋白 卵巢癌的治疗从未成功。 卵巢癌细胞中 MUC16（编码 CA-125 的基因）的特异性转录激活尚不清楚， 并且从未尝试过针对卵巢癌治疗的特异性MUC16反式激活。 尽管如此，我们的总体目标是确定针对 MUC16 基因特异性的可行性 通过开发只能在卵巢中复制的条件复制腺病毒（CRAd）进行反式激活 表达 CA-125 的癌细胞，并测量病毒感染的癌细胞诱导保护性抗- 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 来控制一个必需基因 病毒复制是一种针对卵巢特异性 MUC16 基因反式激活的创新且实用的方法 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来实现总体目标： 目标 1：开发在表达 CA-125 的卵巢癌细胞中特异性复制的有效 CRAd。 目标 2：评估 CRAd 在免疫缺陷和免疫功能正常小鼠中的抗癌活性。 目标 3：选择有效的 CRAd 并评估收集的原发性卵巢癌细胞的溶瘤活性 来自患者。 我们预计构建依赖于 MUC16 反式激活进行复制的 CRAd 的策略将 卵巢癌的治疗可行且有效。成功完成拟议的研究将产生 一种有效的靶向药物，不仅可以特异性地在卵巢癌细胞中复制和裂解，而且还可以激活 保护性抗癌免疫反应。 MUC16 转录元件的更好定义也将奠定 为更详细的卵巢癌中 CA-125 调节机制研究奠定基础，这可能 揭示卵巢癌治疗探索的新靶点。