Optimizing molecular and immunotherapies for the treatment of cholangiocarinoma

胆道系统癌症(BTC)是一种高度侵袭性的肿瘤，在全身姑息治疗下，中位生存期仅为11-13个月。到目前为止，所有在未选定的BTC队列中使用分子疗法的研究都是阴性的。近年来，对胆道肿瘤的分子特征进行了详细的描述，发现胆管肿瘤是一组遗传异质性的恶性肿瘤。然而，这些研究也确定了反复发生的和有针对性的基因改变的子集。最常见的基因突变之一是IDH1基因突变，可在10%-20%的肝内CCA患者中发现，mIDH1抑制剂ivosidenib在Claridhy III期研究中显示出临床疗效。然而，这项研究的批判性评估显示，即使在这种基因定义的BTC患者中，也只有一小部分患者实现了临床上有意义的长期反应。这一观察表明，基因改变的存在并不一定保证对靶向抑制剂的敏感性，并表明存在能够赋予原发抗性的强大分子网络。在不久的将来，该领域可能会转向组合方法，这需要更好地理解可药物基因改变的致癌途径。因此，这项建议的主要目的是将这一临床观察带回“长凳”，并通过我们的临床前小鼠模型和我们的iCCA患者的临床队列来解决这些问题。这项建议的主要目标是更详细地表征mIDH1的作用，以便优化其治疗潜力。在WP 1中，我们将确定mIDH1在肝脏肿瘤发生中对谱系承诺的影响，并剖析共突变谱对肿瘤发生和治疗反应的影响。在WP 2中，我们旨在通过表征下游信号和表观遗传格局的重塑以及鉴定mIDH1结合伙伴来了解突变体IDH的“直接”与2-HG介导的作用。在WP 3中，我们将分析mIDH1如何调节免疫肿瘤微环境(TME)，以及联合检查点和mIDH1抑制对BTC的治疗潜力。最后，我们将继续努力建立一个代表本地CCA患者群体的原发人类患者来源细胞系和异种移植物的代表性生物库。

Cancers of the biliary system (BTC) are highly aggressive tumors with a median survival of only 11 - 13 months under systemic palliative therapy. To date, all studies that employed molecular therapies in unselected BTC cohorts were negative. In recent years, a detailed characterization of the molecular landscape of biliary tumors has been conducted and revealed that BTCs are a genetically heterogeneous group of malignancies. However, these studies also identified a subset of recurrent and targetable genetic alterations. One of the most frequent genetic alterations are mutations in the IDH1 gene, which can be found in 10-20% of patients with intrahepatic CCA, and the mIDH1 inhibitor ivosidenib has shown clinical efficacy in the Claridhy phase-III study. Critical assessment of the study however revealed that even in this genetically defined BTC patients only a subgroup of patients achieves a clinically meaningful long-term response. This observation indicates that the presence of genetic alterations does not necessarily guarantee sensitivity to targeted inhibitors, and points towards the existence of strong molecular networks that are capable of conferring primary resistance. In the near future, the field will likely move towards combination approaches, which requires a better understanding of the oncogenic pathways of the druggable genetic alterations. Therefore, the main aim of this proposal is to take this clinical observation back the “bench” and to address them with our preclinical mouse models and our clinical cohorts of iCCA patients. The main goal of this proposal is to characterize the role of mIDH1 in more detail in order to optimize its therapeutic potential. In WP 1, we will determine the influence of mIDH1 on lineage commitment in liver tumorigenesis and dissect the influence of the co-mutational spectrum on tumorigenesis and therapy response. In WP 2, we aim to understand the “direct” vs. the 2-HG mediated effects of mutant IDH through the characterization of downstream signaling and remodeling of the epigenetic landscape as well as the identification of mIDH1 binding partners. In WP 3, we will analyze how mIDH1 regulates the immune tumor microenvironment (TME) and the therapeutic potential of a combined checkpoint and mIDH1 inhibition in BTC. Finally, we will continue our ongoing efforts to establish a representative biobank of primary human patient derived cell lines and xenografts that represent our local CCA patient population.