TY - JOUR
T1 - Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors
AU - Bartelink, Imke H.
AU - Prideaux, Brendan
AU - Krings, Gregor
AU - Wilmes, Lisa
AU - Lee, Pei Rong Evelyn
AU - Bo, Pan
AU - Hann, Byron
AU - Coppé, Jean Philippe
AU - Heditsian, Diane
AU - Swigart-Brown, Lamorna
AU - Jones, Ella F.
AU - Magnitsky, Sergey
AU - Keizer, Ron J.
AU - de Vries, Niels
AU - Rosing, Hilde
AU - Pawlowska, Nela
AU - Thomas, Scott
AU - Dhawan, Mallika
AU - Aggarwal, Rahul
AU - Munster, Pamela N.
AU - Esserman, Laura J.
AU - Ruan, Weiming
AU - Wu, Alan H.B.
AU - Yee, Douglas
AU - Dartois, Véronique
AU - Savic, Radojka M.
AU - Wolf, Denise M.
AU - van 't Veer, Laura
N1 - Funding 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.
Funding Information:
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.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/9/11
Y1 - 2017/9/11
N2 - 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.
AB - 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.
KW - Carboplatin
KW - Drug penetration
KW - Inductively coupled plasma-mass spectrometry
KW - Matrix-assisted laser desorption/ionization mass spectrometric imaging
KW - Pharmacokinetics
KW - Poly(ADP-ribose) polymerase inhibitors
KW - Spatial heterogeneity
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U2 - 10.1186/s13058-017-0896-4
DO - 10.1186/s13058-017-0896-4
M3 - Article
C2 - 28893315
AN - SCOPUS:85029224863
SN - 1465-5411
VL - 19
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 107
ER -