Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma.
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 apoptosisin vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice. Axitinib also displayed synergistic antitumor activityin vitrowhen 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.
Centre 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.
Lauren T
0000-0001-5290-8289
LT
Kerr
Centre for Cancer Research, Hudson Institute for Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3168, Australia.
Jacqueline F
JF
Donoghue
Centre for Cancer Research, Hudson Institute for Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3168, Australia.
Alexander L
AL
Wilding
Centre for Cancer Research, Hudson Institute for Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3168, Australia.
Terrance G
0000-0002-8874-4543
TG
Johns