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

破译 MYC 相关脆弱性以开发胰腺癌亚组特异性疗法

• 批准号: 317782399
• 负责人: Professor Dr. Günter Schneider
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Kinderchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/317782399?language=en
• 关键词: Deciphering; MYC; assoziated; Vulnerabilities; develop

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.

积极的化疗方案在胰腺导管腺癌（PDAC）的治疗中取得了明显的进步。 PDAC 异质性是开发新疗法的一大障碍。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，即基底样亚型和经典亚型，已得到一致的描述。类似 Basal 的 PDAC 更具攻击性，并且似乎对当前使用的化疗具有抵抗力。致癌转录因子 MYC 的过度激活是一种攻击性亚型的特征，与基底样 PDAC 重叠。明确的证据表明，具有高 MYC 活性的癌症依赖于基因或通路，而临床批准的药物可以针对这些基因或通路。因此，综合致死的概念适合针对此类癌症。我们定义了能够触发 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 中更活跃。一致地，PRMT5被发现与“基底细胞样”癌症有关。我们的目标是通过公正的药物筛选实验找到基于 PRMT5 抑制剂的新型联合疗法，并在初级人类 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护理难治的一组 PDAC 开发一种新疗法的潜力。 II) 最近的研究表明，原代人类 PDAC 细胞响应标准化疗而上调 basal-like 程序和 MYC 网络，从而产生耐药性。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，并适用于系统地研究在第一个资助期定义的针对 MYC 相关脆弱性的药物抑制剂是否也能够针对化疗诱导的耐药 PDAC。在这里，我们看到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。此类工作可以导致二线或序贯疗法的开发。