ImmunoPET Imaging Identifies the Optimal Timepoint for Combination Therapy in Xenograft Models of Triple-Negative Breast Cancer.
ImmunoPET Imaging Identifies the Optimal Timepoint for Combination Therapy in Xenograft Models of Triple-Negative Breast Cancer.
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正在研究用于治疗三阴性乳腺癌（TNBC）的不同组合疗法。达沙替尼就是一种这样的药物，它靶向Src途径杀死癌细胞。然而，达沙替尼治疗还可以增加一种称为糖蛋白非转移性黑色素瘤B（gpNMB）的不同生物标志物的表达，其中TNBC细胞表面高水平的gpNMB与患者的总体生存期较低相关。这种效应可用于增强由结合gpNMB的抗体携带的其他药物（称为抗体药物缀合物）的递送。确定达沙替尼何时增加gpNMB表达对于治疗计划很重要。我们的研究有两个目的。第一个是通过对TNBC小鼠模型中gpNMB的非侵入性成像来评估达沙替尼在多大程度上以及何时增加gpNMB表达。第二个目的是探索gpNMB靶向抗体药物缀合物和达沙替尼的组合治疗在缩小肿瘤方面的功效。这些发现可用于TNBC联合治疗的图像引导方法。(1)目的：糖蛋白非转移性黑色素瘤B（gpNMB）是一种1型跨膜蛋白，在许多癌症中过表达，包括三阴性乳腺癌（TNBC）。其过表达与TNBC患者的总体生存率较低相关。酪氨酸激酶抑制剂（如达沙替尼）可上调gpNMB表达，这有可能增强抗gpNMB抗体药物偶联物（如glembatumumab vedotin（CDX-011））的治疗靶向。我们的主要目的是通过使用89 Zr标记的抗gpNMB抗体（[89 Zr]Zr-DFO-CR 011）进行纵向正电子发射断层扫描（PET）成像，量化Src酪氨酸激酶抑制剂达沙替尼治疗后TNBC异种移植模型中gpNMB上调的程度并确定其时间范围。目的是确定在用达沙替尼治疗后给予CDX-011的时间点，以使用非侵入性成像来增强治疗效果。(2)研究方法：首先，将表达gpNMB（MDA-MB-468）或不表达gpNMB（MDA-MB-231）的TNBC细胞系在体外用2 μM达沙替尼处理48小时，然后对细胞裂解物进行蛋白质印迹分析以确定gpNMB表达的差异。MDA-MB-468异种移植小鼠也每隔一天用10 mg/kg达沙替尼治疗21天。在处理后0、7、14和21天对小鼠亚组实施安乐死，并收获肿瘤用于gpNMB表达的肿瘤细胞裂解物的Western印迹分析。在MDA-MB-468异种移植物模型的不同队列中，在0 ℃处理前用[89 Zr]Zr-DFO-CR 011进行纵向PET成像。（基线）和（1）单独使用达沙替尼（2）CDX-011治疗后14天和28天（10 mg/kg）单独给药，或（3）达沙替尼序贯治疗14天，然后用CDX-011治疗，以确定体内gpNMB表达相对于基线的变化。作为gpNMB阴性对照，在用达沙替尼、CDX-011和达沙替尼的组合以及媒介物对照处理后21天对MDA-MB-231异种移植物模型进行成像。(3)结果如下：MDA-MB-468细胞和肿瘤裂解物的蛋白质印迹分析显示，在治疗开始后14天，达沙替尼在体外和体内增加gpNMB的表达。在MDA-MB-468异种移植小鼠的不同队列的PET成像研究中，肿瘤中的[89 Zr]Zr-DFO-CR 011摄取（SUV平均值= 3.2 ± 0.3）在达沙替尼治疗开始后14天最大与基线时（SUV均值= 3.2 ± 0.3）相比，达沙替尼和CDX-011联合治疗组（SUV均值= 4.9 ± 0.6）或达沙替尼和CDX-011联合治疗组（SUV均值= 4.6 ± 0.2）。在联合给药组中观察到治疗后最高的肿瘤消退，肿瘤体积相对于基线的百分比变化（%CTV）为−54 ± 13，与溶剂对照给药组（%CTV = +102 ± 27）、CDX-011组（%CTV = −25 ± 9.8）和达沙替尼组（%CTV = −23 ± 11）相比。相比之下，MDA-MB-231异种移植小鼠的PET成像表明治疗组（单独的达沙替尼或与CDX-011组合）和媒介物对照组之间[89 Zr]Zr-DFO-CR 011的肿瘤摄取没有显著差异。(4)结论：在治疗开始后14天，达沙替尼上调gpNMB阳性MDA-MB-468异种移植肿瘤中的gpNMB表达，这可以通过用[89 Zr]Zr-DFO-CR 011进行PET成像来定量。此外，达沙替尼和CDX-011的联合治疗似乎是TNBC的一种有希望的治疗策略，值得进一步研究。
Different combination therapies are being investigated for the treatment of triple-negative breast cancer (TNBC). Dasatinib is one such drug that targets the Src pathway to kill cancer cells. However, dasatinib treatment can also increase the expression of a different biomarker called glycoprotein non-metastatic melanoma B (gpNMB), in which high levels of gpNMB on the surface of TNBC cells is associated with lower overall survival of patients. This effect can be exploited to enhance the delivery of other drugs carried by antibodies that bind to gpNMB, known as antibody drug conjugates. Determining when dasatinib increases gpNMB expression is important for treatment planning. The aims of our study are two-fold. The first is to evaluate how much and when does dasatinib increase gpNMB expression through noninvasive imaging of gpNMB in mice models of TNBC. The second aim is to explore the efficacy of the combination treatment with gpNMB-targeted antibody drug conjugate and dasatinib in shrinking the tumor. These findings can be used for image-guided approaches for combination treatments in TNBC. (1) Purpose: The glycoprotein non-metastatic melanoma B (gpNMB) is a type 1 transmembrane protein that is overexpressed in numerous cancers, including triple-negative breast cancer (TNBC). Its overexpression is associated with lower overall survival of patients with TNBC. Tyrosine kinase inhibitors such as dasatinib can upregulate gpNMB expression, which has the potential to enhance therapeutic targeting with anti-gpNMB antibody drug conjugates such as glembatumumab vedotin (CDX-011). Our primary aim is to quantify the degree and identify the timeframe of gpNMB upregulation in xenograft models of TNBC after treatment with the Src tyrosine kinase inhibitor, dasatinib, by longitudinal positron emission tomography (PET) imaging with the 89Zr-labeled anti-gpNMB antibody ([89Zr]Zr-DFO-CR011). The goal is to identify the timepoint at which to administer CDX-011 after treatment with dasatinib to enhance therapeutic efficacy using noninvasive imaging. (2) Methods: First, TNBC cell lines that either express gpNMB (MDA-MB-468) or do not express gpNMB (MDA-MB-231) were treated with 2 μM of dasatinib in vitro for 48 h, followed by Western blot analysis of cell lysates to determine differences in gpNMB expression. MDA-MB-468 xenografted mice were also treated with 10 mg/kg of dasatinib every other day for 21 days. Subgroups of mice were euthanized at 0-, 7-, 14-, and 21-days post treatment, and tumors were harvested for Western blot analysis of tumor cell lysates for gpNMB expression. In a different cohort of MDA-MB-468 xenograft models, longitudinal PET imaging with [89Zr]Zr-DFO-CR011 was performed before treatment at 0 (baseline) and at 14 and 28 days after treatment with (1) dasatinib alone (2) CDX-011 (10 mg/kg) alone, or (3) sequential treatment of dasatinib for 14 days then CDX-011 to determine changes in gpNMB expression in vivo relative to baseline. As a gpNMB-negative control, MDA-MB-231 xenograft models were imaged 21 days after treatment with dasatinib, combination of CDX-011 and dasatinib, and vehicle control. (3) Results: Western blot analysis of MDA-MB-468 cell and tumor lysates showed that dasatinib increased expression of gpNMB in vitro and in vivo at 14 days post treatment initiation. In PET imaging studies of different cohorts of MDA-MB-468 xenografted mice, [89Zr]Zr-DFO-CR011 uptake in tumors (SUVmean = 3.2 ± 0.3) was greatest at 14 days after treatment initiation with dasatinib (SUVmean = 4.9 ± 0.6) or combination of dasatinib and CDX-011 (SUVmean= 4.6 ± 0.2) compared with that at baseline (SUVmean = 3.2 ± 0.3). The highest tumor regression after treatment was observed in the combination-treated group with a percent change in tumor volume relative to baseline (%CTV) of −54 ± 13 compared with the vehicle control-treated group (%CTV = +102 ± 27), CDX-011 group (%CTV = −25 ± 9.8), and dasatinib group (%CTV = −23 ± 11). In contrast, the PET imaging of MDA-MB-231 xenografted mice indicated no significant difference in the tumor uptake of [89Zr]Zr-DFO-CR011 between treated (dasatinib alone or in combination with CDX-011) and vehicle-control groups. (4) Conclusions: Dasatinib upregulated gpNMB expression in gpNMB-positive MDA-MB-468 xenografted tumors at 14 days post treatment initiation, which can be quantified by PET imaging with [89Zr]Zr-DFO-CR011. Furthermore, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC and warrants further investigation.
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影响因子：
2.7
作者：
Taya M;Hammes SR
通讯作者：
Hammes SR
DOI：
10.1158/1078-0432.ccr-16-1192
发表时间：
2016-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rose AA;Annis MG;Frederick DT;Biondini M;Dong Z;Kwong L;Chin L;Keler T;Hawthorne T;Watson IR;Flaherty KT;Siegel PM
通讯作者：
Siegel PM
影响因子：
3.8
作者：
Ocana, Alberto;Gil-Martin, Marta;Ruiz-Borrego, Manuel
通讯作者：
Ruiz-Borrego, Manuel
达沙替尼抑制 c-src 磷酸化并防止过度表达 Syndecan 结合蛋白 (SDCBP) 的三阴性乳腺癌 (TNBC) 细胞的增殖。
影响因子：
3.7
作者：
Qian XL;Zhang J;Li PZ;Lang RG;Li WD;Sun H;Liu FF;Guo XJ;Gu F;Fu L
通讯作者：
Fu L
影响因子：
4
作者：
Maric G;Rose AA;Annis MG;Siegel PM
通讯作者：
Siegel PM