IGF::OT::IGF R&D- MEDICAL: BIOMEDICAL (BASIC RESEARCH)AWARD OF TASK ORDER "OPTIMIZATION AND FURTHER DEVELOPMENT OF MESOTHELIN VACCINE FOR THE PREVENTION OF OVARIAN CANCER"

IGF::OT::IGF R

• 批准号: 9358834
• 负责人: NATHALIE SCHOLLER
• 金额: $ 71.22万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358834
• 关键词: Accounting; Adjuvant; Age; Age-Years; Award; BRCA1 gene; BRCA2 gene; Basic Science; Blood; C-terminal; C57BL/6 Mouse; Cancer Patient; Carcinoma; DNA Sequence Alteration; Development; Diagnosis; Early Diagnosis; Epithelial; Epitopes; Estrogens; Family history of; Female; Genetic Engineering; Genetically Engineered Mouse; Germ-Line Mutation; Growth and Development function; Histology; Hormone replacement therapy; Human; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Individual; Isogeneic graft; Knock-out; Knockout Mice; Link; Loss of Heterozygosity; Lung; MSLN gene; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant mesothelioma; Malignant neoplasm of ovary; Mammalian Oviducts; Medical; Megakaryocytes; Mesothelioma; Mesothelium; Morbidity - disease rate; Mus; Mutation; Obesity; PTEN gene; Pancreas; Pathology; Pathway interactions; Patients; Peptides; Play; Population; Prevention; Preventive; Preventive measure; Protein Precursors; Proteins; Recombinants; Reporting; Reproduction; Risk; Risk Factors; Role; Serous; Serum; Specimen; Splenocyte; Staging; Stomach; Survival Rate; Symptoms; System; Tertiary Protein Structure; Testing; Tumor Antigens; Tumor Tissue; Tumor-Associated Process; Tumor-Derived; United States; Vaccination; Vaccines; Wild Type Mouse; Woman; advanced disease; antitumor effect; base; cohort; endometriosis; high risk; immune function; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; male; malignant breast neoplasm; medical attention; mesothelin; middle age; mortality; mouse model; mutation carrier; offspring; ovarian cancer prevention; ovarian neoplasm; overexpression; parity; protective effect; research and development; screening; survival outcome; tumor; tumor microenvironment; tumorigenic

Ovarian cancer is diagnosed in over 20,000 women in the United States each year. While it accounts only for about 3% of all cancers in women, it is the most lethal gynecologic cancer in this population. The five-year survival rate for women with ovarian cancer remains less than 50%, and it precipitously declines to less than 30% in those diagnosed at 65 years of age or older. The high mortality rate is due in part that there are no effective screening tests currently available, nor early symptoms of ovarian cancer, which prompt patients to seek medical attention. Consequently, the majority of ovarian cancer patients are diagnosed at an advanced stage. While identifying a high-risk cohort and developing better screening strategies is key to early detection and improved survival outcomes, safe and effective preventive measures are also critically needed to further reduce ovarian cancer morbidity and mortality. Risk factors for ovarian cancer include age (middle aged or older), a family history of ovarian cancer, low parity, endometriosis, obesity, a long-term use of estrogen for hormone replacement therapy, and the presence of certain genetic mutations. In particular, highly penetrant germline mutations in BRCA1 and BRCA2 genes have been linked to the increased risk of not only breast cancer but also ovarian cancer. Most ovarian cancers arising in BRCA1/2 mutation carriers are invasive epithelial cancers of serous histology. Emerging evidence points to the fallopian tube as the origin of high grade serous ovarian cancer. One of the mouse models for ovarian cancer developed to date is a genetically engineered conditional Dicer-Pten double knockout (DKO) mouse model reported by Kim et al. The PI3K pathway activating mutations are frequently found in patients with high-grade serous ovarian cancer (HGSOC). Both PTEN and DICER are demonstrated to have frequent allelic loss in the human cancers, and the low DICER levels are often associated with advanced ovarian cancer and poor survival. The conditional DKO mice (Dicerflox/flox;Ptenflox/flox;Amhr2cre/+) developed by Kim et al. develop high-grade serous carcinomas that arise from the fallopian tube, recapitulating human HGSOC pathology. Recent advances in immunotherapies for various cancers have indicated that the immune system can be harnessed to mount robust antitumor immune responses to tumor antigens, if tumor-derived immune suppression in the tumor microenvironment is effectively blocked by immune checkpoint inhibitors. It is highly plausible that the host immune system can be stimulated to generate antitumor immune responses against tumor-associated antigens over-expressed early in the tumorigenic process, where tumor-associated immunosuppressive mechanisms may have a significantly less impact on the host’s immune function than in advanced disease. Mesothelin is physiologically expressed in normal mesothelium, but has been found to be overexpressed in various human cancers, including malignant mesothelioma and cancers of the ovary, pancreas, stomach and lung. It is a 40-kDa protein encoded by the MSLN gene as a C-terminal region of the 71-kDa precursor protein, which also consists of the megakaryocyte potentiating factor (MPF) on the N-terminus. Blood levels of mesothelin and MPF have been shown to be elevated in patients with mesothelioma and ovarian cancer. Although the functional role of mesothelin has yet to be fully elucidated, mesothelin does not seem to play an essential role in growth, development or reproduction, as mesothelin knockout (KO) mice (both males and females) produce offspring normally and have no detectable anatomical or histological abnormalities. Scholler and her colleagues have previously shown through the PREVENT project that vaccination with a recombinant mesothelin protein adjuvanted with CDN/AddaVax elicited humoral and cellular immune responses, which were associated with protective effects against the development of syngeneic ID8 ovarian tumors in C57BL/6 mice. Using the ID8 syngraft and conditional DKO mouse models described earlier, the current project will focus on further development and refinement of mesothelin based vaccine, including the identification of optimal antigenic epitopes and protective immunity, for the prevention of BRCA-driven ovarian cancer.

在美国，每年有超过 20,000 名女性被诊断出卵巢癌，虽然它仅占女性所有癌症的 3% 左右，但它是该人群中最致命的妇科癌症。癌症的发病率仍然低于 50%，并且在 65 岁或以上诊断的人群中急剧下降至低于 30%。高死亡率的部分原因是没有有效的筛查测试。目前，也没有卵巢癌的早期症状，这促使患者寻求医疗检查，但大多数卵巢癌患者在诊断时已处于晚期，而识别高风险人群并制定更好的筛查策略是早期检测的关键。为了改善生存结果，还迫切需要安全有效的预防措施，以进一步降低卵巢癌的发病率和死亡率。 卵巢癌的危险因素包括年龄（中年以上）、卵巢癌家族史、低产次、子宫内膜异位症、肥胖、长期使用雌激素进行激素替代治疗以及存在某些基因突变。 BRCA1 和 BRCA2 基因的渗透性种系突变不仅与乳腺癌风险增加有关，而且与 BRCA1/2 突变携带者发生的卵巢癌风险增加有关。新出现的证据表明输卵管是高级别浆液性卵巢癌的起源。 迄今为止开发的卵巢癌小鼠模型之一是 Kim 等人报道的基因工程条件性 Dicer-Pten 双敲除 (DKO) 小鼠模型。PI3K 通路激活突变常见于高级别浆液性卵巢癌患者。 PTEN 和 DICER 均被证明在人类癌症中经常出现等位基因丢失，并且低 DICER 水平通常与晚期卵巢癌和不良生存相关。 Kim 等人开发的 DKO 小鼠（Dicerflox/flox；Ptenflox/flox；Amhr2cre/+）会发展为源自输卵管的高级浆液性癌，再现了人类 HGSOC 病理学。 各种癌症免疫疗法的最新进展表明，如果免疫检查点抑制剂有效阻断肿瘤微环境中的肿瘤源性免​​疫抑制，则可以利用免疫系统对肿瘤抗原产生强大的抗肿瘤免疫反应。可以刺激宿主免疫系统产生针对在致瘤过程早期过度表达的肿瘤相关抗原的抗肿瘤免疫反应，其中肿瘤相关免疫抑制机制对宿主免疫功能的影响可能明显较小比晚期疾病。 间皮素在正常间皮中生理性表达，但已发现在多种人类癌症中过度表达，包括恶性间皮瘤以及卵巢癌、胰腺癌、胃癌和肺癌。它是由 MSLN 基因编码的 40 kDa 蛋白质。 - 71 kDa 前体蛋白的末端区域，也由巨核细胞增强因子 (MPF) 组成间皮素和 MPF 的 N 末端血液水平已被证明在间皮瘤和卵巢癌患者中升高，尽管间皮素的功能作用尚未完全阐明，但间皮素似乎在生长、发育中并未发挥重要作用。或繁殖，因为间皮素敲除（KO）小鼠（雄性和雌性）都能正常产生后代，并且没有可检测到的解剖或组织学异常。 Scholler 和她的同事之前通过 PREVENT 项目证明，接种以 CDN/AddaVax 为佐剂的重组间皮素蛋白疫苗可引发体液和细胞免疫反应，这与 C57BL/6 小鼠中针对同基因 ID8 卵巢肿瘤发展的保护作用有关。使用前面描述的 ID8 合成移植物和条件 DKO 小鼠模型，当前项目将重点关注基于间皮素的疫苗的进一步开发和完善，包括鉴定最佳抗原表位和保护性免疫，用于预防 BRCA 驱动的卵巢癌。