Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors

Abstract

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.MethodsMDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).ResultsVeliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P < 0.0001).ConclusionsPARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0896-4) contains supplementary material, which is available to authorized users.

Tumor Drug Distribution after Local Drug Delivery by Hyperthermia, In Vivo

“…However, doxorubicin concentrations in the tumor after ThermoDox treatment were inconsistent in this study. For all formulations, an increase in injected dose resulted in a more homogeneous spatial doxorubicin distribution, as was qualitatively observed before for other drugs [44,49].…”

Not only tumor but also therapy heterogeneity

“…Fluorescence microscopy and mass spectrometry imaging (MSI), that can detect drugs with a spatial resolution in the micromolar range, have shown that even small molecule drugs distribute heterogeneously in distinct regions of the same tumor and this has been confirmed in preclinical models and in patient biopsies [40][41][42][43]. These techniques permit analysis of drug localization in relation to tissue architecture.…”

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle

“…At a microscopic level, large molecules or nonionizable agents can be analyzed in a section of the biopsy by immunofluorescence (IF) or multiplexed ion beam imaging, if secondary fluorescent antibodies or those contain isotopically pure elemental metal are available . To assess the spatial distribution of unlabeled small molecules (and their metabolites) in clinical tissue samples, matrix‐assisted laser desorption ionization‐mass spectrometry imaging (MALDI‐MSI) can be applied to a section of a fresh frozen biopsies . By multiplexing (multiple stains per section), other histological assays can be applied to detect other factors in the tumor microenvironment influencing drug penetration (e.g., CD31 immunohistochemistry (IHC) staining for blood vessels).…”