Novel Therapies for Malignant Transformation of Teratomas Based on Comprehensive Genetic Screening

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16831
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Nagoya University
• Principal Investigator: Tamauchi Satoshi 名古屋大学, 医学部附属病院, 助教 (50845097)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 卵巣癌 / 卵巣奇形腫悪性転化 / CRISPR-Cas9スクリーニング

Outline of Final Research Achievements

CRISPR-Cas9 knockout screening was performed using cell lines of ovarian teratoma malignant transformation. Cisplatin was used as a selection pressure for screening. Negative screening revealed 25 genes. Ten genes were identified as novel therapeutic target genes. 10 genes were subjected to knockdown experiments using cell lines and further sorted into 4 genes. Among them, we confirmed that the addition of an inhibitory compound for gene A to the cell lines inhibited cell proliferation. In addition, a xeno-patient population was created by dividing and transplanting tumors from a mouse model derived from a patient with malignant transformation of ovarian teratoma into a large number of nude mice, and intraperitoneal administration of the compound showed significant tumor growth inhibition in the treated group compared to the control group. These results demonstrate the clinical applicability of the therapeutic target genes identified in this screening.

Free Research Field

婦人科悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

本研究では、卵巣奇形腫悪性転化の細胞株を用いたCRISPR-Cas9ノックアウトスクリーニングを通じて、新たな治療標的遺伝子を特定し、その阻害による治療法の有効性を検証した。シスプラチンを選択圧として使用し、遺伝子Aの阻害化合物が細胞増殖を抑制することを確認した。また、患者由来の腫瘍をヌードマウスに移植した疑似患者集団モデルを用いた実験では、同化合物の腹腔内投与により、腫瘍増殖が有意に抑制されることを示した。これにより、本研究で同定された治療標的遺伝子の阻害が新規治療の開発に繋がる可能性が示され、難治性希少がんである本疾患の予後改善につながる社会的意義のある成果が得られた。