Craif Inc. (Location: Bunkyo-ku, Tokyo, CEO: Ryuichi Onose, hereinafter referred to as “Craif”) has signed a joint study agreement with Tokyo Medical University (Location: Shinjuku-ku, Tokyo, Chairman of the Board of Regents: Yoshio Yazaki). With the conclusion of this agreement, Craif and the Urology Department of Tokyo Medical University (Principal Investigator: Dr. Yosuke Hirasawa, Lecturer) will conduct two joint studies to “Explore the Profiling of Urinary miRNA in Urothelial Cancer” and “Develop Biomarkers for the Detection of Small Distant Metastases in Urothelial Cancer Using Urinary miRNA.”

■ Outline of the two studies

1. Exploration of the Profiling of Urinary miRNA in Urothelial Cancer
   The prognosis for advanced bladder cancer is poor, with a 5-year survival rate of only about 5% (*1). Therefore, it is important to detect and diagnose bladder cancer at an early stage, and to intervene with medical treatment before the cancer becomes advanced or metastatic. Though the urine cytology, currently used for diagnosis, has an excellent specificity of 90-100%, it has a poor sensitivity of 40-60%, making it difficult to detect low-grade bladder cancer in particular (*2). Therefore, in actual clinical practice, urine cytology can only be performed with local anesthesia at large hospitals with bladder endoscopy facilities, which is said to be a problem leading to large patient burden, shame, and pain. In recent years, miRNA has attracted attention as a regulatory mechanism for the expression of various genes. 2600 types of miRNA have already been identified which are said to regulate 60% of all the genes. It has also been reported that the expression of miRNA is altered in tumor tissues of cancer patients, resulting in changes in the proliferative ability and viability of cancer cells. In this study, we will analyze and compare urinary miRNA from patients with urothelial carcinoma and healthy people to search for miRNAs whose expression is increased or decreased in a cancer-specific manner, and develop highly accurate urinary biomarkers to detect bladder cancer.
2. Development of Biomarkers for the Detection of Small Distant Metastasis in Urothelial Cancer Using Urinary miRNA
   The standard treatment for muscle layer invasive bladder cancer is total bladder resection, but the 5-year survival rate is only about 50% (*3) (*4), and about 25% of patients develop recurrence or metastasis within 1 year after the surgery (*5). In the case of metastatic case, the 5-year survival rate is as poor as 5% (*1). In particular, cases of metastasis within the first year after surgery are thought to be due to the presence of microscopic distant metastases that cannot be identified by CT or other imaging tests. Currently, cisplatin-based preoperative chemotherapy (neoadjuvant therapy) followed by total bladder resection is becoming the standard treatment (*6) (*7) and has been proven to prolong survival in several randomized controlled trials. However, there are cases in which patients with small distant metastases before surgery should avoid invasive total bladder resection and prioritize systemic treatment such as chemotherapy, but there is no test or biomarker to predict such cases. To solve this problem, this study aims to develop a biomarker to detect small distant metastases before total bladder resection for muscle layer invasive bladder cancer or high-/very high-risk non-muscle invasive bladder cancer. 

Source:
（*1）SEER. Cancer Stat Facts: Bladder Cancer. https://seer.cancer.gov/statfacts/html/urinb.html.
Accessed January 2020.
（*2） Raab SS, Slagel DD, Jensen CS, Teague MW, Savell VH, Ozkutlu D, Lenel JC, Cohen MB.Low-grade transitional cell carcinoma of the urinary bladder: application of select cytologic criteria to improve diagnostic accuracy [corrected] Mod Pathol. 1996;9(3):225-32.
（*3）Stein JP, Lieskovsky G, Cote R, et al：Radical cystectomy in the treatment of invasive bladder cancer：long-term results in 1,054 patients. J Clin Oncol 19：666–675, 2001
（*4） Gore JL, Litwin MS, Lai J, et al：Use of radical cystectomy for patients with invasive bladder cancer. J Natl Cancer Inst 102：802-811, 2010
（*5）Bukhari N, et al. Update on the Treatment of Metastatic Urothelial Carcinoma. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011065/. Accessed January 2020.
（*6） Wang, Y.; Ma, D.L.; Yu, C.H.; Sha, K.F.; Zhao, M.J.; Liu, T.J. MicroRNA-370 suppresses SOX12 transcription and acts as a tumor suppressor in bladder cancer. Eur. Rev. Med. Pharm. Sci. 2020, 24, 2303–2312.
（*7） Griffiths G, Hall R, Sylvester R, et al：International phase Ⅲ trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer：long-term results of the BA06 30894 trial. J Clin Oncol 29 ：2171–2177, 2011