Background: Veliparib is a potent inhibitor of the protein Poly(ADP-ribose) polymerase (PARP). Although effective, in the first clinical trials some TNBC patients fail to respond. We hypothesize that heterogeneous or insufficient drug concentrations in the solid tumor lead to inadequate response to PARPi in some TNBC patients. First we performed a mouse xenograft study to determine the penetration and distribution of veliparib in TNBC tumors in mice.
Methods:MDA.MB.231 cells were injected bilaterally into mamamary fat pad of 10 Beige SCID mice. Veliparib (20mg/kg or 60mg/kg) or placebo was orally administered 3 times daily for 3 days. These doses and dosing schedules were estimated to result in equivalent plasma and tumor concentrations in mice compared to the doses currently used in clinical trials. Mice were euthanized 3 hours after the last dose of veliparib and tumors, liver and muscle tissues were obtained. In addition, control tissues were spiked with a broad range of concentrations of veliparib. The spatial distribution of the drugs in the tumor tissue was measured using Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI). The protonated molecular ion at m/z245.1 was used to construct 2D ion maps of the tissue showing relative quantitation of drug levels. HE staining was performed to characterize the tumors.
Results: Veliparib in control tissues was detected at very low concentrations with a range of detection between 100 fmol-1nmol. After dosing, veliparib penetrates into the tumors and was detectable at both dose levels. However, drug distribution within the tumors was observed to be inhomogeneous. In spots where the drug accumulated, necrosis was observed.
Conclusions: Veliparib can be measured using MALDI with good specificity and sensitivity and using concentrations equivalent to patients. TNBC tumors show largely heterogeneous distribution of PARPi. Future analyses will determine whether this heterogeneity in drug distribution explains variability in response to PARPi therapies.