ABSTRACT

The prognosis of AML is generally poor, with 5-year survival rate of 25%. There has been substantial progress in identification of new therapeutic targets, along with approval of at least three targeted therapies for AML in recent years. Nevertheless, treatment has largely remained unchanged over couple of decades, with ~40% patients not achieving remission. AML is a highly heterogenous disease and there is a need for a preclinical platform to understand the heterogeneity and tumor microenvironment that can guide therapy selection. In this study, we employed an ex vivo tumor explant model to study tumor microenvironment and to select a treatment course for AML patients. Our data reveal dysregulation of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) in a subset of AML patients. Based on this observation, epigenetic modulators azacitidine and panobinostat alone and in combination, were evaluated as treatment regimens in cytarabine refractory tumors. More than 50% of the treated samples showed response to the combination therapy. In order to explore alternate treatment modalities for tumors refractory to these epigenetic modulators, TCGA data analysis was done which revealed increased expression and hypomethylation of IFNGR1/2, suggesting activation of JAK/STAT pathway in AML. This was further interrogated ex vivo, with p-STAT3 expression in patients’ samples. Fedratinib, a JAK/STAT inhibitor was evaluated and 78% tumor efficacy response was achieved. Taken together, our data indicate that ex vivo platform derived from patient samples is capable in guiding optimal therapy selection for various classes of drugs including identification of novel targeted therapies.

摘要

AML的预后普遍较差，5年生存率为25%。近年来，在确定新的治疗靶点方面取得了重大进展，同时批准了至少三种针对 AML 的靶向疗法。尽管如此，几十年来，治疗方法基本保持不变，约 40% 的患者未达到缓解。AML 是一种高度异质性的疾病，需要一个临床前平台来了解可以指导治疗选择的异质性和肿瘤微环境。在这项研究中，我们采用了离体肿瘤外植体模型研究肿瘤微环境并为 AML 患者选择治疗方案。我们的数据揭示了一部分 AML 患者中 DNA 甲基转移酶 (DNMT) 和组蛋白去乙酰化酶 (HDAC) 的失调。基于这一观察，表观遗传调节剂阿扎胞苷和帕比司他单独和联合被评估为阿糖胞苷难治性肿瘤的治疗方案。超过 50% 的处理样本显示出对联合治疗的反应。为了探索对这些表观遗传调节剂难治的肿瘤的替代治疗方式，进行了 TCGA 数据分析，结果显示 IFNGR1/2 的表达增加和低甲基化，表明 AML 中 JAK/STAT 通路的激活。这在体外被进一步询问，p-患者样本中的STAT3表达。对 JAK/STAT 抑制剂 Fedratinib 进行了评估，并实现了 78% 的肿瘤疗效反应。总之，我们的数据表明，源自患者样本的体外平台能够指导各类药物的最佳治疗选择，包括识别新型靶向治疗。