NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer

Abstract

BackgroundBrain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.MethodsFemale nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively).ResultsNKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals.ConclusionsElevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m2 NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1672-4) contains supplementary material, which is available to authorized users.

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

“…This continues to highlight the need to develop novel drug formulations that specifically take advantage of this variable increase in BTB permeability to elevate and extend drug exposure within intracranial metastases. The integration of PEGylation as polymeric anti-cancer formulations, for example, has been shown to extend the plasma half-life of active drug equivalents without increasing toxicity and facilitate distribution to brain tumors by taking advantage of enhanced permeability at the BTB [51]. …”

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model

“…Different from research exploring the mechanism of tumor transplantation and blood metastases as the object of study, this study primarily compared the efficacy of EGFR-TKIs in the treatment of intracranial tumors, for which the direct intracranial transplant method created a more consistent model. Furthermore, whether in drug efficacy studies of metastatic brain tumors or intracranial primary tumors, this type of animal model is widely applied [20, 42, 43]. Secondly, in this study, we did not investigate the potential effect of WBRT on the penetration of EGFR-TKIs into the CSF.…”

Temporary Dysarthria Induced by Irinotecan-Case Report of This Rare Adverse Event

“…However, a study in primates showed that the level of irinotecan in CSF was 14% of the plasma level and SN-38 metabolite cannot be detected intrathecally [10]. Animal models studying the pharmakocinetic properties of pegylated Irinotecan have concluded that there is a prolonged exposure in the CNS compared to conventional irinotecan [13].…”