COT, a new molecular target in refractory B-cell malignancies and its clinical application

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08832
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAGAO TOSHIKAGE 東京医科歯科大学, 東京医科歯科大学病院, 助教 (10622798)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 難治性B細胞腫瘍 / COT（TPL2） / 臨床的バイオマーカー

Outline of Final Research Achievements

ABC-DLBCL is a B-cell lymphoma subtype with relatively unfavorable prognosis. It is characterized by the constitutive activation of NF-κB pathway due to specific mutations in BCR- or TLR-signaling, contributing to the lymphomagenesis. In this project, we identified COT, an intracellular kinase, as a novel drug-able target in ABC-DLBCL. We found that COT/p105 complex, specifically activated by IKK downstream of TLR/MYD88-L265P, promotes activation of NF-κB or MAPK pathway as well as IL-6/IL-10 autocrine loop and resultant JAK/STAT3 activation. In addition, in our results COT accelerated cell cycle progression in ABC-DLBCL by regulating c-MYC and other cell cycle associated molecules. Intriguingly, in IHC-based analysis, high COT expression was significantly associated with relatively worse prognosis among DLBCL patients with ABC phenotype treated in our institute. Together, COT could aid in risk-stratification of ABC-DLBCL and emerge as a new molecular target in this subtype.

Free Research Field

造血器腫瘍

Academic Significance and Societal Importance of the Research Achievements

ABC-DLBCLなど難治性リンパ腫の治療戦略は、NGS関連技術の進歩を背景に新たな時代を迎えている。特に予後不良群においては、細胞起源や特異的遺伝子異常など、より生物学的特性に基いた分子標的の抽出が重要な課題であるが、本研究で我々が見出したCOTは、ABC-DLBCLにおける新たな分子標的として有望である。また他疾患領域では既にCOT阻害薬の臨床応用が見込まれており、将来の抗腫瘍薬の領域への応用も十分に期待できる。また、免疫組織学的染色を用いた解析で、予後不良症例を同定するための臨床的バイオマーカーとしての有用性も示されており、実臨床における治療成績の向上に貢献できる可能性がある。