nvp-ast487 and Breast-Neoplasms

nvp-ast487 has been researched along with Breast-Neoplasms* in 1 studies

Other Studies

1 other study(ies) available for nvp-ast487 and Breast-Neoplasms

Article	Year
Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts. Oncotarget, 2016, Dec-06, Volume: 7, Issue:49 The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Carbanilides; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Letrozole; MCF-7 Cells; Mice, Nude; Molecular Targeted Therapy; Neoplasm Invasiveness; Nitriles; Ovariectomy; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Receptors, Estrogen; Signal Transduction; Spheroids, Cellular; Time Factors; Transfection; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays	2016

Article

Year

Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.

Oncotarget, 2016, Dec-06, Volume: 7, Issue:49

The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Carbanilides; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Letrozole; MCF-7 Cells; Mice, Nude; Molecular Targeted Therapy; Neoplasm Invasiveness; Nitriles; Ovariectomy; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Receptors, Estrogen; Signal Transduction; Spheroids, Cellular; Time Factors; Transfection; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

2016