Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors.
Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors.
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DOI：
10.1186/s13058-017-0896-4
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发表时间：
2017-09-11
期刊：
影响因子：
--
通讯作者：
van 't Veer L
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文献类型：
--
作者：
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
聚（adp -核糖）聚合酶抑制剂（PARPi）与DNA损伤剂偶联是治疗三阴性乳腺癌（TNBC）的一种很有前途的方法。然而，并非所有患者都有反应；我们假设一些患者的无反应可能是由于药物渗透不足。作为验证这一假设的第一步，我们量化并可视化了维利帕里和卡铂在小鼠异种移植tnbc和患者血液样本中的渗透。将MDA-MB-231、HCC70或MDA-MB-436人TNBC细胞植入41只米色SCID小鼠。低剂量（20mg /kg）或高剂量（60mg /kg） veliparib每日三次，连续三天，卡铂（60mg /kg）两次给药。此外，对19例卡铂+ PARPi talazoparib一期研究患者的血液样本进行了分析。采用液相色谱-质谱法（LC-MS）对Veliparib和卡铂进行定量分析。使用基质辅助激光解吸/电离质谱成像（MALDI-MSI）观察Veliparib组织渗透，使用电感耦合等离子质谱（ICP-MS）定量铂加合物（共价核dna结合）。采用药代动力学模型和Pearson相关法探讨血浆、肿瘤细胞和外周血单个核细胞（PBMCs）浓度之间的关系。Veliparib在异种移植肿瘤中的渗透在肿瘤之间和肿瘤内部是高度不均匀的。分别只有35% （CI 95% 26-44%）、74%（40-97%）和46%（9-37%）的veliparib在血浆中渗透到MDA-MB-231、HCC70和MDA-MB-436细胞异种移植物中。在肿瘤内，与20 mg/kg剂量相比，60 mg/kg剂量的穿透异质性更大（RSD分别为155%和255%，P = 0.001）。预测的肿瘤浓度与临床剂量水平相似，但预测的肿瘤浓度低于最大浓度值的一半作为反应阈值。异种移植物veliparib浓度与铂加合物形成呈正相关（r2 = 0.657），但在患者的pbmc中未观察到parpi -铂相互作用。铂加合物形成在5个gBRCA携带者中显著高于9个非携带者(铂在PBMCs/血浆DNA中的比值为0.64% (IQR 0.60-1.16%)，其比值为0.29% （IQR 0.21-0.66%, P < 0.0001）。在pbmc和新鲜冷冻、OCT包埋的核心穿刺活检中，可以通过MALDI-MSI和ICP-MS测量PARPi/铂的肿瘤穿透。铂加合物形成的大变异性和维立帕尼分布的空间异质性可能导致在选择的细胞群中药物暴露不足。本文的在线版本（doi:10.1186/s13058-017-0896-4）包含补充材料，可供授权用户使用。
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. 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). 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). 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. The online version of this article (doi:10.1186/s13058-017-0896-4) contains supplementary material, which is available to authorized users.
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DOI：
10.1097/jto.0b013e3181f38f70
发表时间：
2010-11
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Haura EB;Sommers E;Song L;Chiappori A;Becker A
通讯作者：
Becker A
影响因子：
11.2
作者：
Birkbak NJ;Eklund AC;Li Q;McClelland SE;Endesfelder D;Tan P;Tan IB;Richardson AL;Szallasi Z;Swanton C
通讯作者：
Swanton C
影响因子：
2
作者：
Atkinson, Sally J.;Loadman, Paul M.;Clench, Malcolm R.
通讯作者：
Clench, Malcolm R.
影响因子：
5.8
作者：
Jarvis, Ian W. H.;Meczes, Emma L.;Tilby, Michael J.
通讯作者：
Tilby, Michael J.
影响因子：
4.3
作者：
Buck, Achim;Halbritter, Susanne;Walch, Axel
通讯作者：
Walch, Axel