Department of Molecular & Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, California.
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Mol Cancer Res. 2023 Apr 1;21(4):307-315. doi: 10.1158/1541-7786.MCR-22-0736.
Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels.
hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.
雄激素受体 (AR) 通路激活的非侵入性生物标志物对于更好地监测前列腺癌治疗的患者反应至关重要。AR 是前列腺癌耐药的关键驱动因素和介导因素，但目前用于监测 AR 活性的非侵入性前列腺癌生物标志物与下游 AR 通路活性不一致。外束放射治疗 (EBRT) 仍然是治疗所有阶段前列腺癌的常用方法，EBRT 诱导的 DNA 损伤上调 AR 通路活性以促进治疗耐药性。[89Zr]11B6-PET 是一种靶向前列腺特异性蛋白人激肽释放酶 2 (hK2) 的新型模式，hK2 是 AR 活性的替代生物标志物。在这里，我们研究了[89Zr]11B6-PET 是否可以准确评估 EBRT 诱导的 AR 活性。遗传和人类前列腺癌小鼠模型接受 EBRT（2-50Gy），并通过[89Zr]11B6-PET/CT 监测治疗反应。在切除的组织中定量测定放射性示踪剂摄取和 AR 和 AR 靶基因的表达。EBRT 增加了 LNCaP-AR 和 22RV1 肿瘤中的 AR 通路活性和[89Zr]11B6 摄取。EBRT 增加了前列腺癌荷瘤小鼠（Hi-Myc x Pb_KLK2）中前列腺特异性[89Zr]11B6 的摄取，而在健康（Pb_KLK2）小鼠中摄取没有明显变化，这与 hK2 蛋白水平相关。
前列腺癌组织中 hK2 的表达是 EBRT 诱导的 AR 活性的替代物，可以使用[89Zr]11B6-PET 进行非侵入性检测；进一步临床评估 hK2-PET 以实时监测对 EBRT 的反应和耐药性的发展是有必要的。
