TY - JOUR
T1 - Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models
AU - Kanlikilicer, Pinar
AU - Ozpolat, Bulent
AU - Aslan, Burcu
AU - Bayraktar, Recep
AU - Gurbuz, Nilgun
AU - Rodriguez-Aguayo, Cristian
AU - Bayraktar, Emine
AU - Denizli, Merve
AU - Gonzalez-Villasana, Vianey
AU - Ivan, Cristina
AU - Lokesh, Ganesh L.R.
AU - Amero, Paola
AU - Catuogno, Silvia
AU - Haemmerle, Monika
AU - Wu, Sherry Yen Yao
AU - Mitra, Rahul
AU - Gorenstein, David G.
AU - Volk, David E.
AU - de Franciscis, Vittorio
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
N1 - Publisher Copyright:
© 2017
PY - 2017/12
Y1 - 2017/12
N2 - Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.
AB - Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.
KW - AXL
KW - aptamer
KW - metastasis
KW - ovarian cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85041798465&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2017.06.023
DO - 10.1016/j.omtn.2017.06.023
M3 - Article
C2 - 29246304
AN - SCOPUS:85041798465
SN - 2162-2531
VL - 9
SP - 251
EP - 262
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
ER -