Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Res. 2019 Jan 1;79(1):242-250. doi: 10.1158/0008-5472.CAN-18-2231. Epub 2018 Nov 20.
The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-C] pyruvate to visualize the effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from patients with clear cell RCC (ccRCC) who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. SIGNIFICANCE: These findings demonstrate hyperpolarized pyruvate MRI as a tool for accurately assessing the clinical success of mTOR inhibition in patients with ccRCC.
不断变化的肿瘤微环境不断挑战单个癌细胞来平衡供需，呈现出肿瘤的脆弱性和治疗机会。依维莫司和替西罗莫司是 mTOR（mTORi）的抑制剂，已被批准用于治疗转移性肾细胞癌（mRCC）。然而，mTORi 治疗的效果在患者之间存在很大差异。因此，mRCC 中 mTORi 的应用正在减少，这可能导致部分患者无法及时获得有效的治疗。在这里，我们实施了一个临床适用的、集成的平台，包括单次 [1-C] 丙酮酸剂量，以使用超极化 MRI 可视化 mTORi 对丙酮酸转化为乳酸的影响。使用两种源自对 VEGFRi 原发性耐药且在诊断转移后 6 个月内迅速死于疾病而未接受 mTORi 的 ccRCC 患者的临床前模型，证明了一种可预测治疗效果的显著差异。我们的研究结果表明，超极化 MRI 可以进一步发展，以实现肾癌治疗的个体化。意义：这些发现表明，超极化丙酮酸 MRI 可作为一种工具，用于准确评估 ccRCC 患者中 mTOR 抑制的临床疗效。
