Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225311730210X |
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| author | Pinar Kanlikilicer Bulent Ozpolat Burcu Aslan Recep Bayraktar Nilgun Gurbuz Cristian Rodriguez-Aguayo Emine Bayraktar Merve Denizli Vianey Gonzalez-Villasana Cristina Ivan Ganesh L.R. Lokesh Paola Amero Silvia Catuogno Monika Haemmerle Sherry Yen-Yao Wu Rahul Mitra David G. Gorenstein David E. Volk Vittorio de Franciscis Anil K. Sood Gabriel Lopez-Berestein |
| author_facet | Pinar Kanlikilicer Bulent Ozpolat Burcu Aslan Recep Bayraktar Nilgun Gurbuz Cristian Rodriguez-Aguayo Emine Bayraktar Merve Denizli Vianey Gonzalez-Villasana Cristina Ivan Ganesh L.R. Lokesh Paola Amero Silvia Catuogno Monika Haemmerle Sherry Yen-Yao Wu Rahul Mitra David G. Gorenstein David E. Volk Vittorio de Franciscis Anil K. Sood Gabriel Lopez-Berestein |
| author_sort | Pinar Kanlikilicer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T17:45:34Z |
| format | Article |
| id | doaj.art-30d18358dbe6414f995427ef4aed9541 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-21T17:45:34Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-30d18358dbe6414f995427ef4aed95412022-12-21T18:55:31ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-12-019C25126210.1016/j.omtn.2017.06.023Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer ModelsPinar Kanlikilicer0Bulent Ozpolat1Burcu Aslan2Recep Bayraktar3Nilgun Gurbuz4Cristian Rodriguez-Aguayo5Emine Bayraktar6Merve Denizli7Vianey Gonzalez-Villasana8Cristina Ivan9Ganesh L.R. Lokesh10Paola Amero11Silvia Catuogno12Monika Haemmerle13Sherry Yen-Yao Wu14Rahul Mitra15David G. Gorenstein16David E. Volk17Vittorio de Franciscis18Anil K. Sood19Gabriel Lopez-Berestein20Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USABrown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAIstituto di Endocrinologia ed Oncologia Sperimentale, CNR, 80131 Naples, ItalyDepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USABrown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USABrown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USAIstituto di Endocrinologia ed Oncologia Sperimentale, CNR, 80131 Naples, ItalyDepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADespite 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.http://www.sciencedirect.com/science/article/pii/S216225311730210XAXLaptamermetastasisovarian cancer |
| spellingShingle | Pinar Kanlikilicer Bulent Ozpolat Burcu Aslan Recep Bayraktar Nilgun Gurbuz Cristian Rodriguez-Aguayo Emine Bayraktar Merve Denizli Vianey Gonzalez-Villasana Cristina Ivan Ganesh L.R. Lokesh Paola Amero Silvia Catuogno Monika Haemmerle Sherry Yen-Yao Wu Rahul Mitra David G. Gorenstein David E. Volk Vittorio de Franciscis Anil K. Sood Gabriel Lopez-Berestein Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models Molecular Therapy: Nucleic Acids AXL aptamer metastasis ovarian cancer |
| title | Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models |
| title_full | Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models |
| title_fullStr | Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models |
| title_full_unstemmed | Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models |
| title_short | Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models |
| title_sort | therapeutic targeting of axl receptor tyrosine kinase inhibits tumor growth and intraperitoneal metastasis in ovarian cancer models |
| topic | AXL aptamer metastasis ovarian cancer |
| url | http://www.sciencedirect.com/science/article/pii/S216225311730210X |
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