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

Imke H. Bartelink; Brendan Prideaux; Gregor Krings; Lisa Wilmes; Pei Rong Evelyn Lee; Pan Bo; Byron Hann; Jean Philippe Coppé; Diane Heditsian; Lamorna Swigart-Brown; Ella F. Jones; Sergey Magnitsky; Ron J. Keizer; Niels de Vries; Hilde Rosing; Nela Pawlowska; Scott Thomas; Mallika Dhawan; Rahul Aggarwal; Pamela N. Munster; Laura J. Esserman; Weiming Ruan; Alan H.B. Wu; Douglas Yee; Véronique Dartois; Radojka M. Savic; Denise M. Wolf; Laura van 't Veer

doi:10.1186/s13058-017-0896-4

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

Imke H. Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F. Jones, Sergey Magnitsky, Ron J. Keizer, Niels de Vries, Hilde Rosing, Nela Pawlowska, Scott Thomas, Mallika Dhawan, Rahul Aggarwal, Pamela N. MunsterLaura J. Esserman, Weiming Ruan, Alan H.B. Wu, Douglas Yee, Véronique Dartois, Radojka M. Savic, Denise M. Wolf, Laura van 't Veer

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

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.

Original language	English (US)
Article number	107
Journal	Breast Cancer Research
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s13058-017-0896-4
State	Published - Sep 11 2017
Externally published	Yes

Bibliographical note

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).

Keywords

Carboplatin
Drug penetration
Inductively coupled plasma-mass spectrometry
Matrix-assisted laser desorption/ionization mass spectrometric imaging
Pharmacokinetics
Poly(ADP-ribose) polymerase inhibitors
Spatial heterogeneity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13058-017-0896-4

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594551

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Bartelink, I. H., Prideaux, B., Krings, G., Wilmes, L., Lee, P. R. E., Bo, P., Hann, B., Coppé, J. P., Heditsian, D., Swigart-Brown, L., Jones, E. F., Magnitsky, S., Keizer, R. J., de Vries, N., Rosing, H., Pawlowska, N., Thomas, S., Dhawan, M., Aggarwal, R., ... van 't Veer, L. (2017). Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors. Breast Cancer Research, 19(1), [107]. https://doi.org/10.1186/s13058-017-0896-4

Bartelink, IH, Prideaux, B, Krings, G, Wilmes, L, Lee, PRE, Bo, P, Hann, B, Coppé, JP, Heditsian, D, Swigart-Brown, L, Jones, EF, Magnitsky, S, Keizer, RJ, de Vries, N, Rosing, H, Pawlowska, N, Thomas, S, Dhawan, M, Aggarwal, R, Munster, PN, Esserman, LJ, Ruan, W, Wu, AHB, Yee, D, Dartois, V, Savic, RM, Wolf, DM & van 't Veer, L 2017, 'Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors', Breast Cancer Research, vol. 19, no. 1, 107. https://doi.org/10.1186/s13058-017-0896-4

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title = "Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors",

abstract = "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.",

keywords = "Carboplatin, Drug penetration, Inductively coupled plasma-mass spectrometry, Matrix-assisted laser desorption/ionization mass spectrometric imaging, Pharmacokinetics, Poly(ADP-ribose) polymerase inhibitors, Spatial heterogeneity",

author = "Bartelink, {Imke H.} and Brendan Prideaux and Gregor Krings and Lisa Wilmes and Lee, {Pei Rong Evelyn} and Pan Bo and Byron Hann and Copp{\'e}, {Jean Philippe} and Diane Heditsian and Lamorna Swigart-Brown and Jones, {Ella F.} and Sergey Magnitsky and Keizer, {Ron J.} and {de Vries}, Niels and Hilde Rosing and Nela Pawlowska and Scott Thomas and Mallika Dhawan and Rahul Aggarwal and Munster, {Pamela N.} and Esserman, {Laura J.} and Weiming Ruan and Wu, {Alan H.B.} and Douglas Yee and V{\'e}ronique Dartois and Savic, {Radojka M.} and Wolf, {Denise M.} and {van 't Veer}, Laura",

note = "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: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = sep,

day = "11",

doi = "10.1186/s13058-017-0896-4",

language = "English (US)",

volume = "19",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central",

number = "1",

}

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

UR - http://www.scopus.com/inward/record.url?scp=85029224863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029224863&partnerID=8YFLogxK

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 -

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

Abstract

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