Deciphering MYC-assoziated Vulnerabilities to develop pancreatic cancer subgroup-specific therapies

积极的化疗方案为胰腺导管腺癌（PDAC）的治疗提供了明显的进步。PDAC异质性是开发新疗法的一个实质性障碍。因此，旨在将每个亚型与独特的遗传、表观遗传、代谢、信号传导或临床特征联系起来的亚型分型工作是克服这一障碍的一种方法。PDAC的两种主要亚型，基底样亚型和经典亚型，一直被描述。基底样PDAC更具侵袭性，似乎对目前使用的化疗药物具有耐药性。致癌转录因子MYC的过度激活是一种与基底细胞样PDAC重叠的侵袭性亚型。明确的证据表明，具有高MYC活性的癌症依赖于基因或途径，临床批准的药物可以针对这些基因或途径。因此，合成致死性的概念适用于靶向此类癌症。我们已经确定了能够触发MYC相关漏洞的药物类别。基于这项工作，我们的目标是：I）我们的筛选实验表明，蛋白质精氨酸甲基转移酶5（PRMT5）的抑制剂在具有高MYC活性的PDAC中更有活性。一致地，PRMT5被发现与“基底样”癌症有关。我们的目标是通过无偏倚的药物筛选实验找到新的基于PRMT5受体的联合疗法，并在主要的人类2D、类器官和体内模型中表征和验证疗效。我们看到了为目前标准治疗难治的一组PDAC开发新疗法的潜力。II）最近的工作表明，原代人PDAC细胞上调基底样程序和MYC网络，以响应标准化疗而变得耐药。因此，我们假设MYC激活可能是对靶向和非靶向治疗的默认反应，并应用于系统性研究，靶向第一个资助期定义的MYC相关漏洞的药理学抑制剂是否也能够靶向化疗诱导的耐药PDAC。在这里，我们看到了诱导脆弱性的概念将有助于解决肿瘤内异质性和耐药性的潜力。这样的工作可以导致二线或序贯疗法的发展。

Active chemotherapeutic regimens have provided a clear advance in the therapy of pancreatic ductal adenocarcinoma (PDAC). PDAC heterogeneity is one substantial hurdle to develop new therapies. Therefore, subtyping efforts aiming to connect each subtype with unique genetic, epigenetic, metabolic, signaling, or clinical features is one approach to overcome this hurdle. Two main subtypes of PDAC, the basal-like and the classical subtype, have been consistently described. Basal-like PDACs are more aggressive and seem to be resistant to currently used chemotherapies. Hyperactivation of the oncogenic transcriptionfactor MYC characterizes an aggressive subtype with overlap to basal-like PDACs. Clear evidence demonstrates that cancer with high MYC activity are dependent on genes or pathways, which can be targeted with clinical approved drugs. Therefore, a concept of synthetic lethality is suitable to target such cancers. We have defined classes of drugs able to trigger MYC-associated vulnerabilities. Based on this work we aim for: I) Our screening experiments show that inhibitors of the protein arginine methyltransferase 5 (PRMT5) are more active in PDACs with high MYC activity. Consistently, PRMT5 was found to be connected to “basal-like” cancers. We aim to find novel PRMT5 inhibitor-based combination therapies by an unbiased drug-screening experiment and characterize and validate efficacy in primary human 2D, organoids, and in vivo models. We see the potential to develop a novel therapy for a group of PDACs currently refractory to standard of care. II) Recent work shows that primary human PDAC cells upregulate the basal-like program and the MYC network in response to standard chemotherapies to become resistant. Therefore, we hypothesize that MYC activation might be a default response towards targeted and non-targeted therapies and apply to systematically investigate, whether pharmacological inhibitors targeting MYC-associated vulnerabilities that were defined in the first funding period, are also able to target chemotherapy-induced resistant PDACs. Here, we see the potential that a concept of induced vulnerability will help to address intratumoral heterogeneity and drug resistance. Such work can lead to the development of second line or sequential therapies.