2. Academic Validation
  3. Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma

Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma

  • PLoS One. 2017 Sep 25;12(9):e0185321. doi: 10.1371/journal.pone.0185321.
Kenta Mukaihara 1,  Yu Tanabe 1,  Daisuke Kubota 1,  Keisuke Akaike 1,  Takuo Hayashi 2,  Kaoru Mogushi 3,  Masaki Hosoya 3,  Shingo Sato 4,  Eisuke Kobayashi 5,  Taketo Okubo 1,  Youngji Kim 1,  Shinji Kohsaka 6,  Tsuyoshi Saito 2,  Kazuo Kaneko 1,  Yoshiyuki Suehara 1
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
  • 2 Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
  • 3 Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
  • 4 Department of Physiology and Cell Biology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Tokyo, Japan.
  • 5 Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.
  • 6 Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
PMID: 28945796 DOI: 10.1371/journal.pone.0185321
Abstract

Background: Alveolar soft part sarcoma (ASPS) is an extremely rare metastatic soft tissue tumor with a poor prognosis for which no effective systemic therapies have yet been established. Therefore, the development of novel effective treatment approaches is required. Tyrosine kinases (TKs) are being increasingly used as therapeutic targets in a variety of cancers. The purpose of this study was to identify novel therapeutic target TKs and to clarify the efficacy of TK inhibitors (TKIs) in the treatment of ASPS.

Experimental design: To identify novel therapeutic target TKs in ASPS, we evaluated the antitumor effects and kinase activity of three TKIs (pazopanib, dasatinib, and cabozantinib) against ASPS cells using an in vitro assay. Based on these results, we then investigated the phosphorylation activities of the identified targets using western blotting, in addition to examining antitumor activity through in vivo assays of several TKIs to determine both the efficacy of these substances and accurate targets.

Results: In cell proliferation and invasion assays using pazopanib, cabozantinib, and dasatinib, all three TKIs inhibited the cell growth in ASPS cells. Statistical analyses of the cell proliferation and invasion assays revealed that dasatinib had a significant inhibitory effect in cell proliferation assays, and cabozantinib exhibited marked inhibitory effects on cellular functions in both assays. Through western blotting, we also confirmed that cabozantinib inhibited c-MET phosphorylation and dasatinib inhibited Src phosphorylation in dose-dependent fashion. Mice that received cabozantinib and dasatinib had significantly smaller tumor volumes than control Animals, demonstrating the in vivo antitumor activity of, these substances.

Conclusions: Our findings suggest that cabozantinib and dasatinib may be more effective than pazopanib against ASPS cells. These in vitro and in vivo data suggest that c-MET may be a potential therapeutic target in ASPS, and cabozantinib may be a particularly useful therapeutic option for patients with ASPS, including those with pazopanib-resistant ASPS.

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