PACM-07 PHARMACOLOGIC BLOOD-BRAIN BARRIER MODULATION WITH REGADENOSON IMPROVES DRUG DELIVERY IN BRAIN METASTASIS
Yi Shi, Alyssa Weinstein, Swathi Talluri, Harsh Oza, Ines Godet, David Kamson, Stuart Grossman, Saraswati Sukumar, Daniele GilkesAbstract
Background
Brain metastases are a frequent and clinically devastating complication of metastatic breast cancer, in part because many systemic therapies fail to achieve therapeutic concentrations in the central nervous system (CNS). Regadenoson (Reg), an FDA-approved A2A adenosine receptor agonist used for cardiac stress testing, has been proposed as a pharmacologic modulator of blood-brain barrier (BBB) permeability.
Methods
We evaluated whether Reg enhances CNS delivery of doxorubicin (Dox) and a 70-kDa fluorescent dextran tracer in non-tumor-bearing brain and in models of triple-negative breast cancer (TNBC) brain metastasis. In non-tumor-bearing mice, Reg was administered with Dox to define dose and timing conditions that maximize brain accumulation. Brain delivery was quantified by tissue-based analysis. Macromolecular delivery was assessed using whole-brain imaging of 70-kDa dextran. Reg was then tested in TNBC brain metastasis models, where intralesional Dox accumulation and tumor killing were measured.
Results
Co-administration of Reg with Dox produced the greatest effect, whereas longer lag times reduced efficacy. The optimal Reg dose was 0.005 mg/kg, equivalent to the FDA-approved cardiac stress test dose. At this dose, Reg increased brain Dox accumulation 6-fold in non-tumor-bearing mice versus Dox alone (P < 0.001). Reg also increased the distribution of a 70-kDa dextran by 4.5-fold (P < 0.01). In TNBC brain metastasis models, Dox was not detectable in lesions after Dox alone but became detectable following co-administration with Reg. This was accompanied by a 12- to 16-fold increase in the expression of pro-apoptotic markers γ-H2AX and BAX (P < 0.02) in cancer cells.
Conclusions
Reg transiently enhances CNS drug delivery across both the non-tumor-bearing BBB and the BBB/blood-tumor barrier in TNBC brain metastases, supporting further evaluation as a pharmacologic adjunct to improve therapy for breast cancer brain metastasis.