Molecular Imaging Program, NCI/NIH, Center for Cancer Research, National Cancer Institute, Building 10, Room B3B406, Bethesda, MD, 20892, USA.
Laboratory of Genitourinary Cancer Pathogenesis NCI/NIH, Bethesda, MD, USA.
Mol Imaging Biol. 2021 Oct;23(5):745-755. doi: 10.1007/s11307-021-01605-0. Epub 2021 Apr 23.
PSMA overexpression has been associated with aggressive prostate cancer (PCa). However, PSMA PET imaging has revealed highly variable changes in PSMA expression in response to ADT treatment ranging from increases to moderate decreases. To better understand these PSMA responses and potential relationship to progressive PCa, the PET imaging agent, [F]DCFPyL, was used to assess changes in PSMA expression in response to ADT using genomically characterized LuCaP patient-derived xenograft mouse models (LuCaP-PDXs) which were found to be sensitive to ADT (LuCaP73 and LuCaP136;CS) or resistant (LuCaP167;CR).
[F]DCFPyL (2-(3-{1-carboxy-5-[(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) was used to assess PSMA in vitro (saturation assays) in LuCaP tumor membrane homogenates and in vivo (imaging/biodistribution) in LuCaP-PDXs. Control and ADT-treated LuCaPs were imaged before ADT (0 days) and 2-, 7-, 14-, and 21-days post-ADT from which tumor:muscle ratios (T:Ms) were determined and concurrently tumor volumes were measured (caliper). After the 21-day imaging, biodistributions and histologic/genomic (PSMA, AR) analysis were done.
[F]DCFPyL exhibited high affinity for PSMA and distinguished different levels of PSMA in LuCaP tumors. Post-ADT CS LuCaP73 and LuCaP136 tumor volumes significantly decreased at day 7 or 14 respectively vs controls, whereas the CR LuCaP167 tumor volumes were minimally changed. [F]DCFPyL imaging T:Ms were increased 3-5-fold in treated LuCaP73 tumors vs controls, while treated LuCaP136 T:Ms remained unchanged which was confirmed by day 21 biodistribution results. For treated LuCaP167, T:Ms were decreased (~ 45 %) vs controls but due to low T:M values (<2) may not be indicative of PSMA level changes. LuCaP73 tumor PSMA histologic/genomic results were comparable to imaging/biodistribution results, whereas the results for other tumor types varied.
Tumor responses to ADT varied from sensitive to resistant among these LuCaP PDXs, while only the high PSMA expressing LuCaP model exhibited an increase in PSMA levels in response to ADT. These models may be useful in understanding the clinical relevance of PSMA PET responses to ADT and potentially the relationship to disease progression as it may relate to the genomic signature.
PSMA 的过度表达与侵袭性前列腺癌（PCa）有关。然而，PSMA PET 成像显示，在 ADT 治疗下，PSMA 表达的变化非常大，从增加到适度减少。为了更好地了解这些 PSMA 反应及其与进展性 PCa 的潜在关系，使用了 PET 成像剂 [F]DCFPyL 来评估 ADT 治疗后 PSMA 表达的变化，使用基因组特征明确的 LuCaP 患者来源异种移植小鼠模型（LuCaP-PDXs）进行评估，这些模型对 ADT 敏感（LuCaP73 和 LuCaP136；CS）或耐药（LuCaP167；CR）。
[F]DCFPyL（2-（3-（1-羧基-5-[(6-[F]氟吡啶-3-羰基）-氨基]-戊基）-脲基）戊二酸）用于评估 LuCaP 肿瘤膜匀浆中的 PSMA 体外（饱和测定）和 LuCaP-PDX 中的体内（成像/生物分布）。在 ADT（0 天）前和 ADT 后 2、7、14 和 21 天对对照和 ADT 处理的 LuCaP 进行成像，从这些图像中确定肿瘤：肌肉比值（T:Ms），并同时测量肿瘤体积（卡尺）。在 21 天的成像后，进行生物分布和组织学/基因组（PSMA、AR）分析。
[F]DCFPyL 对 PSMA 具有高亲和力，并能区分 LuCaP 肿瘤中不同水平的 PSMA。与对照相比，ADT 后 CS LuCaP73 和 LuCaP136 肿瘤体积分别在第 7 天或第 14 天明显减少，而 CR LuCaP167 肿瘤体积变化很小。与对照相比，[F]DCFPyL 成像的 T:Ms 在治疗后的 LuCaP73 肿瘤中增加了 3-5 倍，而治疗后的 LuCaP136 T:Ms 保持不变，这与第 21 天的生物分布结果一致。对于治疗后的 LuCaP167，T:Ms 与对照相比下降了约 45%，但由于 T:M 值较低（<2），可能无法说明 PSMA 水平的变化。LuCaP73 肿瘤的 PSMA 组织学/基因组结果与成像/生物分布结果相似，而其他肿瘤类型的结果则有所不同。
在这些 LuCaP PDX 中，肿瘤对 ADT 的反应从敏感到耐药不等，而只有高 PSMA 表达的 LuCaP 模型在 ADT 治疗后表现出 PSMA 水平的增加。这些模型可能有助于理解 PSMA PET 对 ADT 的临床相关性，以及与疾病进展的潜在关系，因为这可能与基因组特征有关。
