Targeting MUC16 transactivation for ovarian cancer treatment

靶向 MUC16 反式激活治疗卵巢癌

• 批准号: 10544193
• 负责人: Edward Wenge Wang
• 金额: $ 24.19万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544193
• 关键词: 19p13.2; Antibodies; Bioinformatics; CA-125 Antigen; Cancer Etiology; Cancer Patient; Cancer cell line; Cessation of life; Chromosomes; Clinical; Collecting Cell; Cytolysis; Cytotoxic agent; DNA; Data; Diagnosis; Disease; Elements; Essential Genes; Firefly Luciferases; Future; Genes; Genetic Transcription; Genomic DNA; Human; Immune response; Immunocompetent; Immunologic Deficiency Syndromes; 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; Transact; Transactivation; Transcriptional Activation; Virus; Virus Replication; Woman; Xenograft procedure; anti-cancer; anticancer activity; cancer cell; cancer therapy; chemotherapy; chimeric antigen receptor; conditionally replicative adenovirus; 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.

摘要 尽管现代进步，卵巢癌仍然是癌症相关死亡的最常见原因之一， 美国的女人。由于缺乏有效的筛查测试，卵巢癌通常在晚期出现， 阶段目前卵巢癌的治疗主要限于手术和化疗， 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超过80%的患者表达高血清CA水平， 125.生物信息学分析表明，CA-125 mRNA在妇科癌细胞中也高度表达， 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已被 被认为是卵巢癌治疗的理想和独特的靶点;然而，靶向CA-125蛋白， 卵巢癌的治疗从未成功过。 卵巢癌细胞中MUC16（编码CA-125的基因）的特异性转录激活作用尚不清楚， 并且从未尝试过靶向特异性MUC16反式激活用于卵巢癌治疗。 尽管如此，我们的总体目标是确定靶向MUC16基因特异性表达的可行性。 通过开发只能在卵巢中复制的条件复制型腺病毒（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- 癌症免疫反应，可用于卵巢癌治疗。 我们假设使用具有MUC16反式激活序列的CRAd来控制一个必需基因， 病毒复制是一种创新和实用的方法，靶向卵巢特异性MUC16基因反式激活， 癌症治疗我们有令人信服的初步数据来支持我们的假设。我们希望完成我们的 通过追求以下具体目标实现总体目标： 目的1：开发在表达CA-125的卵巢癌细胞中特异性复制的有效CRAds。 目的2：评价CRAds在免疫缺陷和免疫正常小鼠体内的抗癌活性。 目的3：选择有效的CRAd并评估在收集的原代卵巢癌细胞中的溶瘤活性 从病人身上。 我们预期构建依赖于MUC16反式激活的CRAd的复制策略将 对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 一种有效的靶向药物，不仅特异性地在卵巢癌细胞中复制和溶解，而且还激活 保护性的抗癌免疫反应。MUC16转录元件的更好定义也将奠定 为更详细地研究卵巢癌中CA-125的调节机制奠定了基础， 揭示了卵巢癌治疗的新靶点。