Elucidation of the inhibitory mechanism of metastasis in bony malignant tumors to realize the early clinical application of FAK inhibitor

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08255
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: University of Miyazaki
• Principal Investigator: Moritake Hiroshi 宮崎大学, 医学部, 教授 (40336300)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 骨肉腫 / ユーイング肉腫 / 転移 / RNAシーケンス / FAK / IGF-IR

Outline of Final Research Achievements

We showed that TAE226, a dual inhibitor of FAK and IGF-IR, has a drastic inhibitory effect on metastasis in Ewing sarcoma. Furthermore, the molecular biological mechanism underlying the effect and the synergetic effect of various anticancer drugs was revealed. We established a mouse model of pulmonary metastasis using the osteosarcoma 143B cell line. RNA from primary and metastatic sites was extracted from mice and two patients, respectively. We compared the expression profile between primary and metastatic sites by RNA sequencing and extracted the 10 most-common genes among high-expression genes at metastatic sites. We then established sgRNA-based knockdown 143B cells for 10 genes and introduced these cells to tibias of immunocompromised mice. One gene showed an inhibitory effect on computed tomography and pathological evaluations at four weeks after inoculation, suggesting its relation to pulmonary metastatic machinery in osteosarcoma.

Free Research Field

小児腫瘍学

Academic Significance and Societal Importance of the Research Achievements

骨原発腫瘍の転移例に対する治療成績の向上は認められていない。今回ユーイング肉腫で見出されたFAKとIGF-IR抑制による転移抑制メカニズム解明は、Novartis社の同薬剤TAE226の開発中止決定は誠に残念であるが、別のルートから臨床応用に繋がっていくことに期待したい。骨肉腫に関しても既存の化学療法の組み合わせでは限界があり、病態メカニズムからアプローチする新規薬剤に期待が集まる。本研究により、現在候補として再現性を確認している遺伝子が標的遺伝子として確定すれば、創薬に繋がり骨肉腫転移症例の予後改善に期待できる。