Nuclear receptors: possible therapeutic targets in combination with HDAC inhibitors for cutaneous T-cell lymphoma

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10166
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kagoshima University
• Principal Investigator: Fujii Kazuyasu 鹿児島大学, 医歯学域附属病院, 講師 (70452571)
• Co-Investigator(Kenkyū-buntansha): 近藤 格 国立研究開発法人国立がん研究センター, 研究所, 分野長 (30284061)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: HDAC阻害剤 / チロシンキナーゼ / 核内受容体 / 皮膚T細胞リンパ腫

Outline of Final Research Achievements

Current therapeutic options for advanced cutaneous T-cell lymphoma (CTCL) are inefficient and there are unmet needs for the novel efficient treatment. The histone deacetylase inhibitors (HDACi) are emerging therapeutic agents for CTCL, while their effects as monotherapy for patients with CTCL are limited. In this study, we focused on nuclear receptors as the targets of combination therapy with HDACi, because HDACi change chromatin structure and may modify the function of the nuclear receptor response elements. We performed the exhaustive protein kinase assay using HDACi and the screening assay using some nuclear receptor agonist with HDACi, and found that HDACi affected some nuclear receptor tyrosine kinase activities; a vitamin D receptor agonist and progesterone receptor agonist and antagonist enhanced HDACi-induced anti-proliferative effects. In conclusion, nuclear receptors are possible therapeutic targets of combination therapy with HDACi for CTCL.

Free Research Field

皮膚リンパ腫、HDAC阻害剤

Academic Significance and Societal Importance of the Research Achievements

進行期皮膚T細胞リンパ腫の治療はいずれも短期的な効果しか期待できない。ヒストン脱アセチル化酵素阻害剤は皮膚T細胞リンパ腫などの新規治療薬で、これまでの治療薬と異なるメカニズムで抗腫瘍効果を示すため治療戦略の中心となりうるが、単剤での効果は限られている。本研究で核内受容体作動薬やチロシンキナーゼ阻害剤にHDAC阻害剤の抗腫瘍効果を増強する作用があることが明らかになったことで、将来的な新規治療法の開発につながる可能性がある。