A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers with a 5-year survival rate of less than 10%. Physicians often rely on biopsy or CT to guide treatment decisions, but these techniques fail to reliably measure the actions of therapeutic agents in PDAC. KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC. A key downstream event of MYC is transferrin receptor (TfR), which has been identified as a biomarker for cancer therapeutics and imaging. In this study, we aimed to test if zirconium-89 transferrin ([89Zr]Zr-Tf) could measure changes in MYC depending on KRAS status of PDAC, and assess target engagement of anti-MYC and anti-ERK targeted therapies. Mice bearing iKras*p53* tumors showed significantly higher (P < 0.05) uptake of [89Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease (P < 0.05) of [89Zr]Zr-Tf uptake in drug vs. vehicle-treated mice bearing Capan-2 and Suit-2 xenografts. IHC analysis of resected PDAC tumors reflects the data observed via PET imaging and radiotracer biodistribution. Our study demonstrates that [89Zr]Zr-Tf is a valuable tool to noninvasively assess oncogene status and target engagement of small molecule inhibitors downstream of oncogenic KRAS, allowing a quantitative assessment of drug delivery.

胰腺导管腺癌（PDAC）是最致命的癌症之一，其5年生存率低于10%。医生通常依靠活检或计算机断层扫描（CT）来指导治疗决策，但这些技术无法可靠地测量治疗药物在胰腺导管腺癌中的作用。超过90%的胰腺导管腺癌存在KRAS突变，并且通过其致癌级联与许多信号通路相关联，包括细胞外调节激酶（ERK）和MYC。MYC的一个关键下游事件是转铁蛋白受体（TfR），它已被确定为癌症治疗和成像的生物标志物。 在这项研究中，我们旨在测试锆 - 89转铁蛋白（[89Zr]Zr - Tf）是否能够根据胰腺导管腺癌的KRAS状态测量MYC的变化，并评估抗MYC和抗ERK靶向治疗的靶点结合情况。 携带iKras*p53*肿瘤的小鼠在诱导性致癌KRAS撤药后，[89Zr]Zr - Tf的摄取量显著升高（P < 0.05）。使用JQ1进行的一项治疗研究表明，在携带Capan - 2和Suit - 2异种移植物的药物治疗组与载体治疗组小鼠中，[89Zr]Zr - Tf的摄取量有统计学意义的降低（P < 0.05）。对切除的胰腺导管腺癌肿瘤进行的免疫组化分析反映了通过正电子发射断层扫描成像和放射性示踪剂生物分布所观察到的数据。 我们的研究表明，[89Zr]Zr - Tf是一种有价值的工具，可用于无创性评估致癌KRAS下游的癌基因状态和小分子抑制剂的靶点结合情况，从而能够对药物递送进行定量评估。