Targeting MiT transcription factors as a novel therapeutic approach to disru pt the adaptive response to microenvironmental stresses that gives rise to d ormant and cancer stem cell

Research Project

Project/Area Number	21K15524
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 50010:Tumor biology-related
Research Institution	University of Tsukuba
Principal Investigator	Louphrasitthiphol Pakavarin 筑波大学, 医学医療系, 助教 (60897081)
Project Period (FY)	2021-04-01 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords	TFEB / TFE3 / PDAC / ISR / OSCAR / Transcription quescence / Dormancy / Phenotypic heterogeneity / Plasticity / MITF/TFEB/TFE3 / Cancer stem cells
Outline of Research at the Start	先端的なメラノーマ研究の知見を、より複雑な難治がんの代表である膵癌の原因解明、治療法開発に展開する。膵癌は乏血性かつ間質の増生により低酸素環境にあり、その生存はTMEとの相互作用を担うTFEB/3依存性である事が分かっている。従って、MITFファミリーを標的とする膵癌治療は、がんのTMEへの応答性を弱める全く新しい切り口の新規の膵癌治療法になる可能性がある。膵癌の3Dオルガのイドライブラリーから、pRNApIIをマーカーとしてCSCの単離を試みる。それらの膵癌CSCにおけるTFEB/3系の関与を明らかにし、その系を阻害する薬剤投与による膵癌の抑制効果、既存薬剤との相乗効果も解析する。
Outline of Final Research Achievements	In the first part, I have verified the initial hypothesis that proteins involve in cellular adaptive response to prevailing stress plays crucial role in cancer cells survival and the ability to thrive under metabolic and therapeutic stress. Through the use of genomics approaches (transcriptomics and genome-wide transcription factors binding site profiling) I have begun to elucidate the underlying molecular pathways associated with the function of the proteins mentioned above. The existence of transcriptionally dormant cells within established isogenic culture cell lines had been demonstrated for the first time. This support the concept of cellular plasticity and highlight the validity of targeting dormant cells to cure patient.
Academic Significance and Societal Importance of the Research Achievements	Should this drug resistant dormant population that is responsible for relapse can be effectively targeted, we can improve overall survival, life quality of the patients (as they will need fewer rounds of chemotherapies) and reduce overall economic burden to the patient and society as a whole.