Identification of hedgehog signal inhibitors in tumors

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08252
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Chiba University
• Principal Investigator: FUJII KATSUNORI 千葉大学, 大学院医学研究院, 特任教授 (70344992)
• Co-Investigator(Kenkyū-buntansha): 宮下 俊之 北里大学, 医学部, 教授 (60174182) ; 塩浜 直 千葉大学, 医学部附属病院, 助教 (10737034)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ヘッジホッグシグナリング / Gorlin 症候群 / PTCH1 / ヘッジホッグ / 基底細胞癌 / 髄芽腫 / 基底細胞母斑症候群 / GLI1

Outline of Final Research Achievements

Hedgehog signaling disorder is usually caused by the abnormal hedgehog signaling due to genetically mutations in these component genes. In this study, we utilized skin fibroblasts derived from the patients with Gorlin syndrome, a hereditary neurocutaneous syndrome with palmar and plantar pits, rib abnormalities, falx calcification, medulloblastoma, and keratocystic odontoid tumors, to this study in order to find novel small compounds which inhibit hedgehog signaling. Dr. Ishibashi, pharmacologist in the Chiba University kindly gave us his natural compound library. We applied these small compounds to the fibroblasts, and analyzed Gli1 mRNA by RT-PCR. We finally found 10 small compounds, and interestingly six compounds had similar central structures. These inhibitory effects were compared to those of cyclopamine and vismodegib, resulting in identifying novel compounds showing anti-signaling effect.

Free Research Field

小児神経学、遺伝性腫瘍

Academic Significance and Societal Importance of the Research Achievements

ヘッジホッグシグナル異常症の効果的阻害薬は将来発症する癌の治療および予防に不可欠である。既存のvismodegibが粘膜症状や消化管障害のために臨床応用が滞る状況で、今回の新たな阻害薬の同定は今後の治療薬確立の第一歩となると考えられる。現在阻害効果の分子的部位の同定のため、PTCH1, SMO, GLI2,およびGLI3のmRA測定を行っており、vismodegibの抑制効果と比較することで臨床応用の可能性について検討している。本経路の異常で発症する基底細胞癌や髄芽腫の今後の治療に新たな展望を与えるとともに、将来のGorlin症候群を始めとする遺伝病治療の契機になることに異議深いと考えられる。