Development of novel therapeutic strategies for pediatric solid tumor based on non-diver gene targeted approaches.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19405
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kyoto University
• Principal Investigator: Takita Junko 京都大学, 医学研究科, 教授 (00359621)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 胎児性腫瘍 / 神経芽腫 / 肝未分化胎児性肉腫 / 肝間葉系過誤腫 / マルチオミクス解析

Outline of Final Research Achievements

There are still many pediatric solid tumor types with poor prognoses, and no effective therapeutic targets have been identified. Unlike adult cancers, the molecular pathogenesis of pediatric solid tumors remains largely unknown due to the low frequency of somatic driver gene mutations. In this study, we performed a multilayered omics analysis to elucidate the molecular pathogenesis of refractory pediatric solid tumors. The results showed that CD144, a cancer stem cell marker, and PHGDH, which is related to serine metabolism, are potential novel therapeutic targets in neuroblastoma. We also found that the pathogenesis of undifferentiated embryonal sarcoma of the liver (UESL) and mesenchymal hamartoma of the liver (MHL) involves elevated miRNA expression due to structural abnormalities of C19MC, and the TP53 pathway is involved in the malignant transformation of UESL.

Free Research Field

小児医学

Academic Significance and Societal Importance of the Research Achievements

小児固形腫瘍は一般的に遺伝子変異が少ないことから、臨床的多様性を規定する分子病態が十分に解明されていなかった。本研究によって、胎児性腫瘍である神経芽腫において、遺伝子変異によらないCD144およびPHGDHが新規治療標的となりうることが示され、また肝未分化胎児性肉腫では、均一な分子病態を有することが明らかとなった。本研究の成果により、胎児性腫瘍の臨床的多様性の分子病態の理解が一段と深まった。本成果は、小児がん領域において開発が進まなかったがん免疫治療の提案に寄与し、更にmiRNAクラスターであるC19MC領域の機能の解明の一助にも貢献するものであり、臨床的かつ学術的なインパクトは大きい。