2022 Fiscal Year Final Research Report

Analysis of NOTCH and PROP1 as new therapeutic targets in high-risk pituitary adenomas

Research Project

PDF

Project/Area Number	20K09360
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56010:Neurosurgery-related
Research Institution	Research Institute, Shiga Medical Center
Principal Investigator	Hojo Masato 滋賀県立総合病院(研究所), その他部局等, 科長 (60372588)
Co-Investigator(Kenkyū-buntansha)	谷垣健二滋賀県立総合病院(研究所), 神経病態研究部門, 専門研究員 (70362473) 丹治正大京都大学, 医学研究科, 助教 (50766657)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	Prop1 / Notch / VEGF / OSI-930 / 難治性下垂体腺腫 / クッシング病
Outline of Final Research Achievements	Although Anti-VEGF therapy may be an alternative treatment for refractory pituitary adenomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Prop1 is the first pituitary specific transcription factor in pituitary development, and is related to the Notch pathway. In this study, we first examined the expression of PROP1 in corticotroph adenomas. PROP1 was prominently expressed in less differentiated corticotroph adenomas. This result suggests that PROP1 may have a role in tumorigenesis of pituitary adenomas, and is expected to be a new therapeutic target for refractory pituitary adenomas. Next, we found that mice administered with OSI-930, an inhibitor of VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This result demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.
Free Research Field	脳神経外科学
Academic Significance and Societal Importance of the Research Achievements	ACTH産生下垂体腺腫において、分化の程度の低い腺腫細胞にPROP1が高率に発現していることを示し、PROP1が難治性下垂体腺腫の治療標的となる可能性を示した。Prop1に関連する因子としてNotch、Notchに関連する因子としてVEGF着目し、VEGF受容体の阻害により高率に下垂体に出血をきたすことを示した。本研究で、VEGF受容体阻害薬の投与により下垂体卒中を生じるリスクがあることを初めて示すことができた。このことは、抗VEGF療法の下垂体血管に対する作用の解明につながり、難治性下垂体腺腫の新たな治療法を開発するための礎となると考えられる。