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Published on: September 30, 2016
Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma
Lauren T Kerr1, Jacqueline F Donoghue2, Alexander L Wilding2
1Centre for Cancer Research, Hudson Institute for Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; The Ritchie Centre, Hudson Institute for Medical Research, 27-31 Wright St, Clayton, VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3168, Australia.
Abstract:
Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice. Axitinib also displayed synergistic antitumor activity in vitro when combined with the potassium channel ionophore salinomycin or the BH3 mimetic ABT-737. Another angiogenesis-targeting therapeutic, 4EGI-1, which targets the oncoprotein eIF4E, significantly decreased angiogenic ligand expression by myxoid liposarcoma cells and reduced tumor cell growth. To verify this oncogenic addiction to angiogenic pathways, we utilized VEGFR-derived ligand traps and found that autocrine VEGFR signaling was crucial to myxoid liposarcoma cell survival. Overall, these findings suggest that autocrine angiogenic signaling through the VEGFR family is critical to myxoid liposarcoma cell survival and that further study of axitinib as a potential anticancer therapy is warranted.
Insights
Targeting angiogenesis with axitinib shows promise for treating myxoid liposarcoma, a rare cancer. This research reveals that blocking vascular endothelial growth factor receptor (VEGFR) signaling is crucial for tumor cell survival, suggesting axitinib as a potential therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Myxoid liposarcoma is a rare soft-tissue sarcoma with a significant relapse rate, necessitating novel therapeutic strategies.
- Understanding the underlying tumor biology is crucial for developing effective treatments for recurrent myxoid liposarcoma.
Purpose of the Study:
- To identify novel treatment regimens for myxoid liposarcoma by screening targeted therapeutics and chemotherapeutics.
- To investigate the role of angiogenesis and identify potential therapeutic targets in myxoid liposarcoma.
Main Methods:
- Screening of targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines.
- In vitro and in vivo evaluation of axitinib, a small molecule inhibitor targeting VEGFR, PDGFR, and c-Kit.
- Assessment of combination therapies involving axitinib with salinomycin or ABT-737.
- Utilizing VEGFR-derived ligand traps to investigate autocrine VEGFR signaling.
Main Results:
- Targeting angiogenesis demonstrated significant antitumor activity against myxoid liposarcoma.
- Axitinib inhibited cell cycle progression, induced apoptosis in vitro, and reduced tumor growth in xenograft models.
- Axitinib exhibited synergistic effects when combined with salinomycin or ABT-737.
- 4EGI-1 reduced angiogenic ligand expression and tumor cell growth.
- Autocrine VEGFR signaling was identified as critical for myxoid liposarcoma cell survival.
Conclusions:
- Autocrine angiogenic signaling via the VEGFR family is essential for myxoid liposarcoma cell survival.
- Axitinib demonstrates potential as an anticancer therapy for myxoid liposarcoma, warranting further investigation.
- Combination therapies may enhance the efficacy of axitinib in treating myxoid liposarcoma.
