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.

抽象的 尽管有现代的进步，卵巢癌仍然是与癌症相关死亡的最常见原因之一 在美国的妇女。由于缺乏有效的筛查测试，卵巢癌通常会出现在晚期 阶段。目前对卵巢癌的治疗主要仅限于手术和化学疗法，五年 生存率低于50％。迫切需要新的治疗方法来帮助患者患有这种致命的患者 疾病。卵巢癌的一个独特特征是，超过80％的患者表现出高血清的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却没有。 CA-125已经过去了 被视为卵巢癌治疗的理想和独特目标；但是，靶向Ca-125蛋白 卵巢癌的治疗从未成功。 卵巢癌细胞中MUC16的特定转录激活（编码Ca-125的基因）的定义很差， 从未尝试过针对特定的MUC16进行卵巢癌治疗的反式激活。 然而，我们的总体目标是确定针对MUC16基因特异性的可行性 通过开发有条件复制的腺病毒（CRAD）的反式激活，该腺病毒只能在卵巢中复制 表达CA-125并衡量病毒感染的癌细胞诱导保护性抗抗菌的能力的癌细胞 可以利用卵巢癌治疗的癌症免疫反应。 我们假设使用与MUC16反式激活序列的Crad控制基本基因的基因 病毒复制是针对特定MUC16基因反式激活的创新且实用的方法 癌症治疗。我们拥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 通过追求以下特定目标，总体目标： 目标1：开发出在表达CA-125的卵巢癌细胞中专门复制的有效围栏。 AIM 2：评估CRAD在免疫缺陷和免疫能力小鼠中的抗癌活性。 AIM 3：选择有效的CRAD并评估收集的原发性卵巢癌细胞中的溶瘤活性 来自患者。 我们预计，构建CRAD的策略取决于MUC16进行复制的反式激活 对于卵巢癌治疗是可行且有效的。成功完成拟议的研究将产生 有效的靶向剂，不仅在卵巢癌细胞中特异性复制和裂解，而且激活 保护性抗癌免疫反应。 MUC16转录元素的更好定义也将放置 对卵巢癌的CA-125调节进行更详细的机械调查的基础工作，这可能 揭示新的靶标，以探索卵巢癌治疗。