Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids.
Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids.
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DOI：
10.18632/oncotarget.24425
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发表时间：
2018-02-27
期刊：
影响因子：
--
通讯作者：
Hasan T
中科院分区：
文献类型：
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作者：
Broekgaarden M;Rizvi I;Bulin AL;Petrovic L;Goldschmidt R;Massodi I;Celli JP;Hasan T
晚期转移性疾病的有效治疗仍然是无法手术的胰腺癌管理的主要挑战。目前的治疗，如奥沙利铂（OxPt）为基础的化疗方案（FOLFIRINOX）提供了适度的短期生存改善，但具有显着的毒性。光动力疗法（PDT）是一种光激活的癌症疗法，已显示出胰腺癌治疗的临床前景，并增强了常规化疗的非重叠毒性。本研究调查了使用临床批准的光敏剂苯并卟啉衍生物（BPD，维替泊芬）的新辅助PDT增强转移性胰腺癌中OxPt功效的能力。在器官型三维（3D）培养物中评价治疗效果，器官型三维（3D）培养物是弥补常规细胞培养物和体内模型之间差距的临床代表性模型。时间间隔的多参数分析表明，PDT+OxPt联合治疗的上级疗效优于每种单药治疗，这在不同器官型胰腺癌培养物中得到了重现。新辅助PDT对OxPt化疗的治疗益处以时间依赖性方式实现，以单独使用OxPt或PDT无法实现的方式减少残留活组织和肿瘤活力。这些发现强调了智能组合疗法和相关模型的需要，以评估机械不同治疗之间相互作用的时间动力学，并突出了PDT作为播散性胰腺癌新辅助治疗的前景。
Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinically-approved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporally-spaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanistically-distinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer.