Clarification of mechanisms for inhibition of retinoblastoma growth by CEP-1347

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18870
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Yamagata University
• Principal Investigator: Keita Togashi 山形大学, 医学部, 病院助教 (80810796)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 網膜芽細胞腫 / CEP1347 / MDM4 / p53

Outline of Final Research Achievements

Retinoblastoma is the most common pediatric intraocular malignancy. Although retinoblastoma has become one of the malignant tumors with a good prognosis due to the development of various treatment methods, the rate of eye preservation in severe cases is still low. In addition, chemotherapy and radiotherapy involve the risk of secondary cancer development, and novel therapies that are safe and preserve visual function are strongly needed.
The present study revealed that CEP1347, a drug developed for the Parkinson's disease, has a potent growth inhibitory effect on retinoblastoma cells in which p53, a representative tumor suppressor gene, is wild-type and the MDM4 gene, a p53 suppressor gene, is amplified.
Furthermore, we found that one of the molecular mechanisms of the inhibitory effect of CEP1347 on retinoblastoma cells is the activation of p53 by suppressing MDM4 expression.

Free Research Field

眼腫瘍

Academic Significance and Societal Importance of the Research Achievements

網膜芽細胞腫は幼少期に発症するため患児の長い人生において著しい視機能障害ひいてはQOLの低下をもたらす疾患である。多くの網膜芽細胞腫において、代表的ながん抑制遺伝子p53が野生型であることが知られており、加えてp53の抑制因子の一つであるMDM4遺伝子は約65%の症例において増幅しているとの報告もある。本研究ではCEP1347がp53野生型かつMDM4高発現している網膜芽細胞腫症例において抗腫瘍効果を持つことを明らかにし、近い未来、多くの網膜芽細胞腫患者に対して有用な新規分子標的治療の1選択肢となる可能性を提言した。