Development of novel therapeutic approaches based on the elucidation of disease specific metabolism in osteosarcoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07247
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hoshi University
• Principal Investigator: Shimizu Takatsune 星薬科大学, 薬学部, 准教授 (40407101)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨肉腫 / 転移巣 / 治療抵抗性 / 代謝

Outline of Final Research Achievements

Novel therapies for refractory osteosarcoma (OS) must be developed. We focused on metabolism and performed metabolome analyses using our unique mouse model. Glycolysis and protein synthesis were upregulated in metastatic cells. Consistent with this, cytarabine exhibited a potent antitumor effect. Based on metabolite levels, non-adherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified trametinib that preferentially decreased the viability of non-adherent cells. Notably, activation status of several kinases and crosstalk between MEK-ERK and PI3K-AKT pathways varied in OS, that might determine the response to MEK inhibition. A single dose of trametinib decreased primary tumors and CTCs. Moreover, combined administration of trametinib and anticancer drugs was effective for metastasis.
Thus, combination of trametinib and agents targeting metabolism such as cytarabine holds therapeutic potential for treatment of OS.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

難治性悪性腫瘍である骨肉腫は、特に転移巣の治療が今なお困難である。そこで、独自に樹立した骨肉腫マウスモデルを用いて肺転移巣の細胞内代謝を解析し、その知見をもとに分子標的療法を用いた新たな治療法の選択肢を開発した。具体的には、がん細胞の生存に必要なMEK-ERK細胞シグナルの阻害と核酸合成代謝の阻害は、転移巣を含め強い抗腫瘍効果を認めることが明らかとなった。代謝解析と遺伝子発現解析、薬剤スクリーニングを組み合わせた解析は、骨肉腫など独特の性質を有する希少悪性疾患の新規治療法開発に有効である可能性が示唆された。