Development of a two-step molecular targeted therapy to eliminate gastric cancer stem cells and progenitor cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03667
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokai University
• Principal Investigator: Suzuki Hidekazu 東海大学, 医学部, 教授 (70255454)
• Co-Investigator(Kenkyū-buntansha): 佐藤 智典 慶應義塾大学, 理工学部(矢上), 教授 (00162454) ; 津川 仁 東海大学, 医学部, 講師 (30468483) ; 土居 信英 慶應義塾大学, 理工学部(矢上), 教授 (50327673)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 胃がん幹細胞 / CD44 / H. pylori / オートファジー / mucosoid / 胃内共生細菌

Outline of Final Research Achievements

Analysis of the mucosoid model, which is a two-dimensional development of gastric organoids, showed that butyric acid, a short-chain fatty acid with HDAC inhibitory activity, markedly increased CAPZA1 expression, and under H. pylori infection, CagA accumulated in a CAPZA1 expression-dependent manner. Furthermore, we confirmed the existence of commensal bacteria other than H. pylori that confer intragastric butyrate environment in human gastric juice. On the other hand, we obtained human VH single-domain antibodies that specifically bind to CAPZA1 and developed a technology that can deliver them into the nucleus while maintaining the binding activity of the antibodies. In addition, by using a ternary complex of luciferase gene/chitosan/hyaluronic acid, we obtained intracellular transduction of genes specific to CD44v9-positive cells, microtubule-dependent transport to the nucleus, and gene expression activity.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

癌幹細胞標的療法は治療抵抗性癌を根本的に克服する革新的癌治療戦略として大いに期待される。そこで本研究では、CAPZA1を標的し、胃癌幹細胞の発生を抑制し、かつ治療する技術を開発した。これまでの癌幹細胞を標的する癌治療戦略では常に分子標的マテリアルの開発に難航してきたが、独自のmRNAディスプレイ法や膜透過促進ペプチドを駆使することでCAPZA1の標的マテリアルを開発した。
CAPZA1過剰発現細胞、およびCD44v9陽性癌幹細胞を標的とした次世代分子標的バイオ医薬を開発し、「癌幹細胞/前駆細胞選択的二段階駆逐型新規癌治療戦略」の確立を推進したことは学術的・社会的の両面で非常に有意義であった。