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，每年有超过2万名女性被诊断出患有卵巢癌。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生存率仍然低于50%，而在65岁或以上被诊断为卵巢癌的女性中，五年生存率急剧下降至不到30%。高死亡率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，这些症状会促使患者寻求医疗照顾。因此，大多数卵巢癌患者在晚期被诊断出来。虽然确定高危人群和制定更好的筛查策略是早期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来进一步降低卵巢癌的发病率和死亡率。

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.