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"

在美国，每年有2万多名女性被诊断为卵巢癌。虽然它只占女性所有癌症的3%左右，但它是这一人群中最致命的妇科癌症。患有卵巢癌的女性的五年存活率仍然不到50%，而65岁或以上确诊的女性的五年存活率急剧下降到30%以下。死亡率高的部分原因是目前没有有效的筛查测试，也没有卵巢癌的早期症状，这促使患者寻求医疗救治。因此，大多数卵巢癌患者被诊断为晚期。虽然确定高危人群和制定更好的筛查策略是及早发现和改善生存结果的关键，但也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(中年或老年)，卵巢癌家族史，低生育，子宫内膜异位症，肥胖，长期使用雌激素进行激素替代治疗，以及某些基因突变的存在。特别是，BRCA1和BRCA2基因的高渗透性种系突变不仅与乳腺癌风险增加有关，还与卵巢癌风险增加有关。大多数发生在BRCA1/2突变携带者的卵巢癌是浆液性组织学浸润性上皮癌。新的证据表明，输卵管是高级别浆液性卵巢癌的起源。 迄今为止发展起来的卵巢癌小鼠模型之一是Kim等人报道的遗传工程条件性DICER-PTEN双基因敲除(DKO)小鼠模型。高级别浆液性卵巢癌(HGSOC)患者常发现PI3K通路激活突变。在人类癌症中，PTEN和DICER都被证明存在频繁的等位基因丢失，并且低水平的DICER通常与晚期卵巢癌和低生存期相关。由Kim等人建立的条件性DKO小鼠(Dicerflx/Flox；Ptenflx/Flox；Amhr2cre/+)。发生于输卵管的高级别浆液性癌，重述人类HGSOC的病理。 各种癌症免疫治疗的最新进展表明，如果免疫检查点抑制剂有效地阻断肿瘤微环境中的肿瘤源性免疫抑制，就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。在肿瘤形成过程的早期，肿瘤相关抗原的过度表达可以刺激宿主免疫系统产生抗肿瘤免疫反应，而肿瘤相关免疫抑制机制对宿主免疫功能的影响可能比晚期疾病小得多。 Mesothelin在正常间皮细胞中生理性表达，但已被发现在多种人类癌症中过表达，包括恶性间皮瘤以及卵巢癌、胰腺癌、胃癌和肺癌。它是由MSLN基因编码的一个40 kDa的蛋白，是71 kDa前体蛋白的C末端区域，也包括N末端的巨核细胞增强因子(MPF)。间皮瘤和卵巢癌患者的血液中间皮蛋白和MPF水平升高。虽然间硫蛋白的功能作用尚未完全阐明，但间硫蛋白似乎在生长、发育或生殖中并不起重要作用，因为间硫蛋白基因敲除(KO)小鼠(包括雄性和雌性)正常生育后代，并且没有可检测到的解剖或组织学异常。 Scholler和她的同事们之前通过预防项目表明，用CDN/AddaVax佐剂的重组间皮蛋白接种可诱导体液和细胞免疫反应，这与防止C57BL/6小鼠发生同基因ID8卵巢肿瘤有关。利用前面描述的ID8同种移植物和条件性DKO小鼠模型，目前的项目将专注于进一步开发和完善基于间硫蛋白的疫苗，包括鉴定最佳抗原表位和保护性免疫，以预防BRCA驱动的卵巢癌。

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.