Schulte Michael L, Hight Matthew R, Ayers Gregory D, Liu Qi, Shyr Yu, Washington M Kay, Manning H Charles
Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Mol Imaging Biol. 2017 Jun;19(3):421-428. doi: 10.1007/s11307-016-1008-z.
This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[F]fluoroglutamine (4-[F]F-GLN) positron emission tomography (PET) to predict response to BRAF-targeted therapy in preclinical models of colon cancer.
Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC.
Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF-targeted therapies are ineffective.
4-[F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
本研究旨在探讨癌细胞与周围正常细胞相比是否具有独特的代谢特征，如谷氨酰胺摄取增加。鉴于此，谷氨酰胺摄取的定量测量可能反映肿瘤学中的关键过程。约10%的结直肠癌（CRC）患者表达BRAF ，这可以通过选择性BRAF抑制剂或与互补信号轴抑制剂联合使用来进行治疗。在这种情况下，针对这些靶向治疗的非侵入性和定量预测措施仍未得到充分发展。本研究的主要目的是探索4-[F]氟谷氨酰胺（4-[F]F-GLN）正电子发射断层扫描（PET）在结肠癌临床前模型中预测对BRAF靶向治疗的反应。
使用来自原发性人类结肠癌患者（n = 115）和CRC肝转移患者（n = 111）的肿瘤微阵列，通过免疫组织化学评估肿瘤学中主要的谷氨酰胺转运体ASCT2的患病率。随后，在表达人类BRAF 和BRAF野生型CRC的小鼠模型中评估4-[F]F-GLN PET。
约70%的原发性结肠癌和53%的转移瘤表现出ASCT2免疫反应阳性，表明[F]4-F-GLN PET可能适用于大多数结肠癌患者。ASCT2表达与突变型BRAF的表达没有选择性关联。在BRAF 突变的Colo-205肿瘤中，4-[F]F-GLN降低预测了对单药BRAF以及BRAF与PI3K/mTOR联合抑制的药理反应。相比之下，在BRAF野生型HCT-116肿瘤中未观察到类似的降低，在这种情况下BRAF靶向治疗无效。
与2-脱氧-2[F]氟-D-葡萄糖PET相比，4-[F]F-GLN PET选择性地反映了对BRAF抑制的药效学反应，2-脱氧-2[F]氟-D-葡萄糖PET在所有治疗队列中均非特异性降低，无论下游途径抑制情况如何。这些发现说明了谷氨酰胺摄取的非侵入性PET成像测量在选择性预测结肠癌对BRAF靶向治疗反应方面的实用性，并可能提示在使用针对MAPK激活的靶向疗法为结肠癌临床试验提供信息方面有进一步的机会。
