Abstract P6-11-02: Spatial distribution of veliparib measured by matrix assisted laser desorption ionization mass spectrometry in triple negative breast cancer tumors

Background: Veliparib, an inhibitor of Poly(ADP-ribose) polymerase (PARPi), in combination with DNA-damaging agents showed significant efficacy, especially in triple negative breast cancer (TNBC) patients. However, in I-SPY 2, approximately 42% of TNBC did not optimally respond to the veliparib based treatment. To exert therapeutic effect, drugs such as veliparib or the DNA damaging agent carboplatin must reach cancer cells at an adequate concentration. Differences within the microenvironment of the tumor (e.g. reduced vascular density and leaky endothelium) are responsible for variability in the uptake and distribution of the drug in the tumor. 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 and carboplatin in TNBC tumors in mice. Methods: 1*106 MDA.MB.231, HCC70 or MDA.MB.436 cells were injected bilaterally into mamamary fat pad of a total of 36 Beige SCID mice. When the tumors exceeded 200 mm3, veliparib (20mg/kg or 60mg/kg) or placebo was orally administered 3 times daily for 3 days + Carboplatin 60mg/kg on day 1+2. These doses and dosing schedules were estimated to result 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, 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/z 245.1 was used to construct 2D ion maps of the tissue showing relative quantitation of drug levels. HE San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-02.