2024年胰腺癌研究及诊疗新进展

doi:10.19401/j.cnki.1007-3639.2025.01.001

摘要/Abstract

摘要：

胰腺癌是一种恶性程度极高的恶性肿瘤，其发病率自2000年以来呈缓慢增长趋势。尽管诊疗水平的提升促使胰腺癌患者的5年生存率相较于50年前有了一定提高，但仍是预后不容乐观的恶性肿瘤之一。步入2024年，胰腺癌早期筛查策略、疾病机制探索、临床诊疗方案等研究领域取得了诸多进展，并显示出良好的临床应用前景。早期筛查方面，人工智能（artificial intelligence，AI）技术赋能胰腺癌早诊、早筛，使临床诊疗踏上新台阶；此外，液体活检等技术的准确率提升，为胰腺癌早筛提供了新方向。疾病发病机制研究方面，3D基因组映射技术揭示了胰腺导管上皮内瘤变（pancreatic intraepithelial neoplasm，PanIN）的多克隆起源和遗传异质性。基础研究方面，模拟胰腺癌独特结构特征的分支器官模拟系统为胰腺癌体外研究提供了新模型；肿瘤重要代谢物乳酸将胰腺癌代谢微环境与表观遗传学改变联系在一起，揭示了潜在治疗靶点；组蛋白H3K36三甲基转移酶SETD2缺陷导致胰腺癌内源性表观遗传失调，并促进线粒体氧化磷酸化（oxidative phosphorylation，OXPHOS）和肿瘤进展；基质细胞与癌细胞间信号分子血小板衍生生长因子受体（platelet-derived growth factor receptor，PDGFR）轴形成双向分泌回路，或能成为治疗新靶点；嵌合抗原受体巨噬细胞（chimeric antigen receptor macrophage，CAR-M）靶向c-MET的疗法展现出与化疗药物协同增效的潜力；胰腺癌微环境中的巨噬细胞通过CCL5/TRAF6/核因子-κB（nuclear factor-κB，NF-κB）通路促进胰腺癌恶病质进展，表明巨噬细胞有望成为预测及干预胰腺癌恶病质发生、发展的有效靶点。诊疗方面，新辅助化疗后手术可改善可切除与交界可切除患者的总生存（overall survival，OS），但仍需进一步优化新辅助化疗方案；首个临床有效的KRAS^G12D靶向药物已见报道，广谱KRAS突变体抑制剂研究不断涌现；通过糖酵解相关评分（glycolysis-related scores，GRS）进行患者分层能够进一步指导治疗方案选择；“智能外泌体”（Exo^Smart）通过增强细胞摄取能力协助提高化疗效果；免疫治疗联合化疗临床试验的实施，有望协同提高胰腺癌疗效；派安普利单抗和安罗替尼联合白蛋白结合型紫杉醇/吉西他滨（PAAG）在一线转移性胰腺癌（metastatic pancreatic cancer，mPC）患者中显示出较好的疗效和安全性；靶向KRAS突变编码新抗原的癌症疫苗ELI-002 2P能够诱导抗肿瘤免疫反应；溶瘤腺病毒疗法能够协同化疗药物提高晚期胰腺导管腺癌患者的疗效。本文就2024年度胰腺癌基础研究和诊疗领域的最新重大进展进行综述。

关键词: 胰腺癌, 流行病学, 基础研究, 临床研究

Abstract:

Pancreatic cancer is a highly malignant tumor, and its incidence rate has been slowly increasing since 2000. Although the improvement of diagnosis and treatment has led to an increase in the five-year survival rate of pancreatic cancer compared to 50 years ago, it remains one of the discouraging tumor diseases regarding its prognosis. In 2024, many achievements were made in the research of early screening, disease mechanism, clinical diagnosis and treatment of pancreatic cancer, showing a good prospect for clinical application. In early screening, artificial intelligence (AI) technology has empowered early diagnosis and screening of pancreatic cancer, pushing clinical diagnosis and treatment to a new level. Additionally, improvements in the accuracy of technologies such as liquid biopsy have provided new directions for early screening of pancreatic cancer. In terms of research on disease pathogenesis, 3D genome mapping technology has revealed the polyclonal origin and genetic heterogeneity of pancreatic intraepithelial neoplasm (PanIN). In basic research, a branched organ simulation system that mimics the unique structural characteristics of pancreatic cancer provides a new model for in vitro studies of pancreatic cancer. Lactate, an important tumor metabolite, links the metabolic microenvironment of pancreatic cancer with epigenetic changes, revealing potential therapeutic targets. Defects in the histone H3K36 trimethyltransferase SETD2 contribute to endogenous epigenetic dysregulation in pancreatic cancer and promote mitochondrial oxidative phosphorylation (OXPHOS) and tumor progression. The platelet-derived growth factor receptor (PDGFR) axis, which facilitates communication between stromal cells and cancer cells, forms a bidirectional secretory circuit and may become a new therapeutic target. Chimeric antigen receptor macrophage (CAR-M) therapy targeting the tyrosine kinase receptor c-MET demonstrates potential for synergistic enhancement with chemotherapy drugs. Macrophages in the pancreatic cancer microenvironment promote the development of pancreatic cancer cachexia through the CCL5/TRAF6/nuclear factor-κB (NF-κB) pathway, suggesting that macrophages could be an effective target for predicting and intervening in the development of pancreatic cancer cachexia. In terms of advancements in diagnosis and treatment, surgery following neoadjuvant chemotherapy can improve overall survival (OS) in resectable and borderline resectable patients, but further optimization of neoadjuvant chemotherapy protocols is needed. The first clinically effective KRAS^G12D-targeted drug has been reported, and research on inhibitors of a wide range of KRAS mutants is continually emerging. Patient stratification based on glycolysis-related scores (GRS) can further guide the selection of treatment protocols. “Intelligent exosomes” (Exo^Smart) enhance cellular uptake capacity to assist in improving chemotherapy efficacy. The implementation of clinical trials combining immunotherapy with chemotherapy is expected to synergistically improve the efficacy of pancreatic cancer treatment. Pembrolizumab and anlotinib combined with albumin-bound paclitaxel/gemcitabine (PAAG) have shown great efficacy and safety in first-line treatment of metastatic pancreatic cancer (mPC) patients. The cancer vaccine ELI-002 2P, which targets KRAS mutation-encoded neoantigens, can induce an antitumor immune response. Oncolytic adenovirus therapy can synergistically improve the efficacy of treatment in advanced pancreatic ductal adenocarcinoma patients when combined with chemotherapy. This article reviewed the latest major progress in the field of basic research and diagnosis and treatment of pancreatic cancer in 2024.

Key words: Pancreatic cancer, Epidemiology, Basic research, Clinical research

中图分类号:

R735.9

王婷, 秦毅, 徐晓武, 虞先濬. 2024年胰腺癌研究及诊疗新进展[J]. 中国癌症杂志, 2025, 35(1): 1-11.

WANG Ting, QIN Yi, XU Xiaowu, YU Xianjun. New advances in basic research, clinical diagnosis and treatment of pancreatic cancer in 2024[J]. China Oncology, 2025, 35(1): 1-11.

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