Background: Poly(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. Methods: MDA-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). Results: Veliparib 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). Conclusions: PARPi/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.
Bibliographical noteFunding Information:
This research was supported by a grant from the UCSF Helen Diller Family Comprehensive Cancer Center Breast Oncology Program, Mount Zion Health Fund and the Pharmacogenomics Development Core funds. Dr Bartelink received funding from the Ruth L. Kirschstein National Research Service Award T32 NIH grant, 5T32GM0075446. The MALDI-MSI imaging was supported by the National Institute of Health: 1S10OD018072-01A1. Samples from the UCSF Helen Diller Family Comprehensive Cancer Center Tissue Core and Susan G. Komen Tissue Bank at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, and the donors and their families, whose help and participation made this work possible. The content is solely the responsibility of the authors.
This study was supported by a grant from the UCSF Helen Diller Family Comprehensive Cancer Center Breast Program. Dr Bartelink received funding from the Ruth L. Kirschstein National Research Service Award T32 NIH grant, 5T32GM007546. The MALDI-MSI imaging was supported by the National Institute of Health: 1S10OD018072-01A.
© 2017 The Author(s).
- Drug penetration
- Inductively coupled plasma-mass spectrometry
- Matrix-assisted laser desorption/ionization mass spectrometric imaging
- Poly(ADP-ribose) polymerase inhibitors
- Spatial heterogeneity