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.
Highlights
Brain metastases are an increasing problem in women with invasive breast cancer
The vasculature associated with brain metastases (BTB) becomes compromised resulting in elevated permeability compared to normal blood– brain barrier (BBB); the extent of BBB opening following its disruption by the formation of brain metastasis is limited, preventing small molecule chemotherapeutics to reach efficacious levels in the majority of metastatic lesions [17]
NKTR-102 prolongs survival of animals with breast cancer brain metastases Having established that NKTR-102 distributes to brain metastases of breast cancer (BMBC), we evaluated whether elevated concentrations of NKTR-102 in BM would translate to improved survival in an experimental model of BMBC
Summary
Strategies designed to treat brain metastases of breast cancer, chemotherapeutics such as irinotecan, demonstrate limited efficacy. A major obstacle for effective chemotherapeutic activity against BM is drug penetration across the blood– brain barrier (BBB) and the blood-tumor barrier (BTB). The BBB serves as a protective interface that sequesters the brain from undesired chemicals by utilizing physical barriers, efflux transporters, and enzymatic degradation. Together, these components functionally regulate brain penetration of numerous small and large molecules such as anticancer drugs [15]; it is estimated that less than 2 % of drugs targeting the CNS enter clinical trials because of inefficient distribution into brain [16]. The vasculature associated with brain metastases (BTB) becomes compromised resulting in elevated permeability compared to normal BBB; the extent of BBB opening following its disruption by the formation of brain metastasis is limited, preventing small molecule chemotherapeutics to reach efficacious levels in the majority of metastatic lesions [17]
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