Abstract C61: Non-homogeneous drug penetrance of veliparib measured in triple negative breast tumors
Authors: Bartelink Imke H. , Prideaux Brendan , Krings Gregor , Wilmes Lisa , Lee Pei R.E. , Hann Byron , Coppé Jean-Philippe , Heditsian Diane , Swigart-Brown Lamorna , Jones Ella F. , Magnitsky Sergey , Keizer Ron , Esserman Laura , Ruan Weiming , Wu Alan , Yee Douglas , Dartois Veronique , Wolf Denise , Savic Rada , vantVeer Laura 
Published: May 2016

Abstract
Background: Veliparib, an inhibitor of Poly(ADP-ribose) polymerase (PARPi), in combination with carboplatin showed efficacy in triple negative breast cancer (TNBC) patients in the I-SPY 2 TRIAL. However ∼42% of TNBC did not achieve pathologic complete response. Insufficient uptake of drug in TNBC may lead to inadequate response to PARPi. As a first step toward testing this hypothesis in patients, we quantified veliparib penetration in mouse xenograft models of TNBC.
Methods: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Veliparib at low dose (20mg/kg) or high dose (60mg/kg) and carboplatin (60mg/kg) was given three times daily for three days. MR images were taken at day 1. Plasma, fresh frozen and OCT embedded tissues were analyzed using Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI) Liquid chromatography–mass spectrometry (LC-MS). Drug penetration was compared among doses and cell lines.
Results: Ex vivo veliparib concentrations quantified by LC-MS differed significantly among the tumors derived from the three cell lines. Liver and plasma concentrations were uniformly high in all mice compared to tumor and muscle tissues. Plasma pharmacokinetics in mice exhibited non-linear clearance resulting in prolonged high plasma levels at higher doses, while tumor and plasma concentrations were linearly correlated. MALDI-MSI images of tumor and muscle in 12 mice showed higher veliparib concentrations in necrotic areas compared to areas with viable tumor cells (P = 0.126, Table) and higher concentrations at the rim then in the center of the tumor (P = 0.046). Lower concentrations were found in MDA-MB-231 than in other cell lines (0.008). Contrast agent and veliparib accumulated near the rim of the tumors and a fast elimination of the contrast agent from the tumor correlated with relatively low veliparib tumor concentrations.
Conclusions: The spatial distribution of veliparib in TNBC depends on the dose and tumor cell biology. We demonstrated that MALDI-MSI can be used to measure veliparib penetration tumor samples, which may have potential to monitor response to PARPi therapies.
Table: Veliparib concentrations by LC-MS and its spatial distribution by MALDI varies by tissue, drug dose and TNBC cell line of origin.
TissueNMedian conc. (mg/L)RSEPMethodPlasma low/high dose9/60.19 / 0.8610%/11%0.001 (low/high dose)LC-MSTNBC xenograft tissue19/170.05 / 0.3356% / 12%0.322 (tumor/plasma)LC-MSMuscle5/60.12 / 0.4770% / 47%0.882 (muscle/plasma)LC-MSLiver6/60.47 / 1.7720% / 14%&lt;0.001 (liver/plasmaLC-MSnecrotic tissue/ cellular tumor tissue19/191.63 / 1.0170% / 85%0.126MALDIrim/ center19/191.54 / 1.1389% / 87%0.046MALDIHCC70 / MDA-MB-231 / MDA-MB-4366/7/60.31/ 0.12/0.1418% / 22% / 49%0.008LC-MS
Citation Format: Imke H. Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei R.E. Lee, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F. Jones, Sergey Magnitsky, Ron Keizer, Laura Esserman, Weiming Ruan, Alan Wu, Douglas Yee, Veronique Dartois, Denise Wolf, Rada Savic, Laura vantVeer. Non-homogeneous drug penetrance of veliparib measured in triple negative breast tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C61.