Sharma Ajay Kumar, Gupta Kuldeep, Mishra Akhilesh, Lofland Gabriela, Chen Sophia Y, Marsh Ian, Fair Peyton T, Hobbs Robert F, Armstrong Todd M, Jaffee Elizabeth M, Gabrielson Edward W, Zheng Lei, Nimmagadda Sridhar
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Theranostics. 2025 Mar 18;15(10):4229-4246. doi: 10.7150/thno.106948. eCollection 2025.
Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in oncology due to its aggressive nature and resistance to therapy. Current treatments, including surgery, chemotherapy, and radiotherapy, have limited success in improving patient outcomes. This study addresses the urgent need for novel radiotheranostic strategies for PDAC by investigating EphA2 as a potential target. Analysis of genomic data from the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) revealed elevated EphA2 expression in PDAC, confirmed by immunohistochemical staining of tumor tissue microarrays (TMAs). Further analysis showed variable EphA2 expression across PDAC cell lines, with surface receptor density not always correlating with mRNA levels. A low molecular weight peptide was developed and labeled with gallium-68 for PET imaging. studies demonstrated specific binding to EphA2-expressing PDAC cells with rapid internalization. PET imaging in subcutaneous and orthotopic PDAC models confirmed high tumor uptake and minimal off-target binding, confirming EphA2 as a valid imaging target. For molecular radiotherapy, a DOTA-conjugated peptide was labeled with the alpha-particle emitter, actinium-225. studies revealed dose-dependent cytotoxicity in PDAC cells, with an IC of 0.32 µCi/mL. In a tumor model, treatment with Ac-225 labeled peptide significantly inhibited tumor growth compared to controls, with mild adverse effects. These results establish EphA2 as a promising radiotheranostic target in PDAC, with potential for both non-invasive imaging and targeted radiotherapy. Given the potential, further optimization of EphA2-targeted agents are warranted to advance personalized treatment strategies for PDAC patients.
胰腺导管腺癌（PDAC）因其侵袭性和对治疗的抗性，在肿瘤学领域构成了巨大挑战。包括手术、化疗和放疗在内的现有治疗方法，在改善患者预后方面成效有限。本研究通过将EphA2作为潜在靶点进行研究，满足了对PDAC新型放射诊疗策略的迫切需求。对癌症细胞系百科全书（CCLE）和癌症基因组图谱（TCGA）的基因组数据分析显示，PDAC中EphA2表达升高，肿瘤组织微阵列（TMA）的免疫组织化学染色证实了这一点。进一步分析表明，不同的PDAC细胞系中EphA2表达存在差异，表面受体密度并不总是与mRNA水平相关。开发了一种低分子量肽并用镓 - 68进行标记用于PET成像。研究表明其能与表达EphA2的PDAC细胞特异性结合并迅速内化。皮下和原位PDAC模型中的PET成像证实肿瘤摄取高且非靶向结合最少，证实EphA2是一个有效的成像靶点。对于分子放疗，一种与DOTA偶联的肽用α粒子发射体锕 - 225进行标记。研究显示在PDAC细胞中具有剂量依赖性细胞毒性，IC为0.32 μCi/mL。在肿瘤模型中，与对照组相比，用Ac - 225标记的肽治疗显著抑制了肿瘤生长，且副作用轻微。这些结果表明EphA2是PDAC中有前景的放射诊疗靶点，具有非侵入性成像和靶向放疗的潜力。鉴于此潜力，有必要进一步优化EphA2靶向制剂，以推进针对PDAC患者的个性化治疗策略。
