Optimizing molecular and immunotherapies for the treatment of cholangiocarinoma

胆道系统癌症（BTC）是高度侵袭性的肿瘤，全身姑息治疗的中位生存期仅为11 - 13个月。迄今为止，所有在BTC队列中采用分子疗法的研究都是阴性的。近年来，对胆道肿瘤的分子景观进行了详细的表征，发现BTC是一组遗传异质性的恶性肿瘤。然而，这些研究也确定了一个子集的复发性和有针对性的遗传改变。最常见的遗传改变之一是IDH 1基因突变，可在10-20%的肝内CCA患者中发现，mIDH 1抑制剂ivosidenib在Claridhy III期研究中显示出临床疗效。然而，该研究的关键评估显示，即使在这种遗传定义的BTC患者中，也只有一个亚组的患者达到了有临床意义的长期缓解。这一观察结果表明，遗传改变的存在并不一定保证对靶向抑制剂的敏感性，并指向存在能够赋予原发性耐药性的强大分子网络。在不久的将来，该领域可能会转向组合方法，这需要更好地了解可药物遗传改变的致癌途径。因此，本提案的主要目的是将该临床观察结果带回“实验室”，并使用我们的临床前小鼠模型和iCCA患者的临床队列来解决这些问题。该提案的主要目标是更详细地描述mIDH 1的作用，以优化其治疗潜力。在WP 1中，我们将确定mIDH 1对肝肿瘤发生中谱系定型的影响，并分析共突变谱对肿瘤发生和治疗反应的影响。在WP 2中，我们的目标是通过表征下游信号传导和表观遗传景观的重塑以及鉴定mIDH 1结合伴侣来理解突变IDH的“直接”与2-HG介导的效应。在WP 3中，我们将分析mIDH 1如何调节免疫肿瘤微环境（TME）以及联合检查点和mIDH 1抑制BTC的治疗潜力。最后，我们将继续我们正在进行的努力，以建立一个代表性的生物库的主要人类患者来源的细胞系和异种移植，代表我们当地的CCA患者群体。

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.