pazopanib and Triple-Negative-Breast-Neoplasms

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Kidney Neoplasms; Mice; Mice, SCID; Mice, Transgenic; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients.

Topics: Administration, Metronomic; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Blotting, Western; Cell Line, Tumor; Female; Gene Expression; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Indazoles; Kaplan-Meier Estimate; Mice; Mice, SCID; Neoplasm Proteins; Neovascularization, Pathologic; Pyrimidines; Real-Time Polymerase Chain Reaction; Sulfonamides; Topotecan; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays