Development of new combined chemotherapy with mutant p53 function recovery drug for esophageal cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18118
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Kobayashi Teruyuki 大阪大学, 医学系研究科, 招へい教員 (70779751)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 食道扁平上皮癌 / PRIMA-1MET / 5-FU / p53 / p73 / NOXA

Outline of Final Research Achievements

The TP53 gene mutation rate in esophageal squamous epithelial cancer has been reported to be 90% or more, and is involved in chemotherapy resistance. In the p53 missense mutant strain, PRIMA-1MET showed an antitumor effect more than the additive effect when combined with any anticancer agent, and particularly showed a synergistic effect when used in combination with 5-FU. Apoptosis was strongly induced by this combination therapy, and the expression of p53, p73, and NOXA was enhanced. Even in subcutaneous tumor model mice using p53 missense mutant strain (TE8) and PDX model mice using human-derived cells, the antitumor effect was clearly stronger in the 5-FU + PRIMA-1MET combination group than in each single agent administration. Increased expression of p73 / NOXA was observed in the tumor tissue after treatment.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

食道扁平上皮癌におけるTP53遺伝子変異率は9割以上といわれ、化学(放射線)療法の耐性や予後に関与する。PRIMA-1METは、2002年に小分子化合物スクリーニングで同定されとくにp53ミスセンス変異の転写能を回復するとされるが、食道扁平上皮癌する治療効果、メカニズムの一端、化学療法との併用効果が明らかとなった。今後、食道扁平上皮癌に対して、個別医療・オーダーメード医療を改良するにあたって、治療選択肢の一助を担う有意義な成果であると考えられる。