Dynamic changes during the treatment of pancreatic cancer.
Dynamic changes during the treatment of pancreatic cancer.
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DOI：
10.18632/oncotarget.24483
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发表时间：
2018-03-13
期刊：
影响因子：
--
通讯作者：
Levine AJ
中科院分区：
文献类型：
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作者：
Wolff RA;Wang-Gillam A;Alvarez H;Tiriac H;Engle D;Hou S;Groff AF;San Lucas A;Bernard V;Allenson K;Castillo J;Kim D;Mulu F;Huang J;Stephens B;Wistuba II;Katz M;Varadhachary G;Park Y;Hicks J;Chinnaiyan A;Scampavia L;Spicer T;Gerhardinger C;Maitra A;Tuveson D;Rinn J;Lizee G;Yee C;Levine AJ
这篇手稿对一位胰腺癌患者进行了为期五年的跟踪调查，详细介绍了临床记录、病理、分子和细胞变化的动态演变以及对化疗、靶向治疗和免疫治疗的反应。来自活组织检查和血液的DNA和RNA样本确定了一组动态变化的等位基因失衡和拷贝数变化对治疗的反应。从一段时间的活检建立的有机培养被用于广泛的药物测试，以确定这种方法是否可行的治疗。当检测到不寻常的药物反应时，采用广泛的RNA测序分析来建立该药物的新作用机制。器官细胞培养被用来识别可能与肿瘤相关的抗原，并针对其中一种抗原扩增患者的T细胞。在最初的活检和扩大的T细胞群体中观察到相似和相同的T细胞受体序列。免疫治疗未能缩小肿瘤，因为在治疗之前，肿瘤已经经历了上皮向间质的转变。对转移性肺肿瘤进行温暖的尸检，可以在五年的治疗和手术中对肿瘤的异质性进行广泛的分析。这种对肿瘤的临床描述、影像、病理、分子和细胞进化、治疗以及对化疗、靶向治疗和免疫治疗的反应的详细分析，以及为单个患者开发个性化医疗治疗的尝试，应该为未来癌症治疗的方向提供有价值的指导。
This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.