SFB 1243: Genetic and Epigenetic Evolution of Hematopoietic Neoplasms

SFB 1243：造血系统肿瘤的遗传和表观遗传进化

• 批准号: 278529602
• 金额: --
• 依托单位: Ludwig-Maximilians-Universität München (LMU)
• 依托单位国家: 德国
• 项目类别: Collaborative Research Centres
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/278529602?language=en
• 关键词: SFB; 1243; Genetic; Epigenetic; Evolution

The major challenge in cancer therapy is the capacity of tumors to evolve and thereby escape selection pressures imposed by the body and by therapies. This evolutionary process is fueled by random genetic and epigenetic changes, making tumors with their billions of cells a diverse and moving target. Any therapy therefore needs to capture and tackle the molecular heterogeneity of tumor cells in different cancers and individual patients to ensure lasting success. Especially in the era of molecularly targeted cancer therapies, anticipating possible escape routes and effectively blocking them by suitable drug combinations and/or dosing regimens is critical. Informed treatment decisions are ideally based on a comprehensive understanding of how genetic and epigenetic alterations and the clonal composition of tumors determine the evolution of therapy resistance and which specific vulnerabilities can be exploited. The close integration of clinical, molecular, computational and evolutionary expertise within this CRC enables us to identify, quantify and model the molecular processes and parameters that lead to the initial emergence of hematopoietic neoplasms, their evolution towards therapy resistance and the influence of the microenvironment. Within this CRC, we coordinately study myeloid and lymphoid neoplasms focusing on myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), follicular lymphoma (FL), multiple myeloma (MM) and mantle cell lymphoma (MCL). We study clonal hematopoiesis and its underlying epigenetic mechanisms, the role of the bone marrow niche and the immune microenvironment, the rate and mechanism of (epi)genetic evolution with and without drug treatment and disease resistance mechanisms to apoptosis inducers, antibody-based immunotherapies and proteasome inhibitors. As there is no single perfect model system, we take an integrated approach combining cell culture systems, xenotransplantation models and genetically modified mice, all closely linked with the analysis of patient-derived material and data from clinical trials. We are convinced that this interdisciplinary approach will promote a better understanding of the basic processes of tumor evolution and ultimately improve therapy and patient outcomes.

癌症治疗中的主要挑战是肿瘤进化的能力，从而逃脱身体和治疗施加的选择压力。这一进化过程是由随机的遗传和表观遗传变化推动的，使拥有数十亿细胞的肿瘤成为多样化和移动的目标。因此，任何治疗方法都需要捕捉和解决不同癌症和个体患者中肿瘤细胞的分子异质性，以确保持久的成功。尤其是在分子靶向癌症治疗的时代，预测可能的逃逸途径并通过合适的药物组合和/或剂量方案有效地阻止它们是至关重要的。知情的治疗决定理想的基础是全面了解遗传和表观遗传变化以及肿瘤的克隆组成如何决定治疗耐药性的演变以及可以利用哪些特定的脆弱性。临床、分子、计算和进化方面的专业知识在这个CRC中的紧密结合使我们能够识别、量化和模拟导致造血肿瘤最初出现的分子过程和参数、它们向治疗耐药的演变以及微环境的影响。在这项研究中，我们协调研究髓系和淋巴系肿瘤，重点是骨髓增生异常综合征(MDS)、急性髓系白血病(AML)、滤泡性淋巴瘤(FL)、多发性骨髓瘤(MM)和套细胞淋巴瘤(MCL)。我们研究了克隆性造血及其潜在的表观遗传学机制，骨髓生态位和免疫微环境的作用，有无药物治疗的(Epi)遗传进化的速度和机制，以及对凋亡诱导剂、基于抗体的免疫治疗和蛋白酶体抑制剂的抗病机制。由于没有单一的完美模型系统，我们采取了结合细胞培养系统、异种移植模型和转基因小鼠的综合方法，所有这些都与患者来源的材料和临床试验数据的分析密切相关。我们相信，这种跨学科的方法将促进更好地了解肿瘤进化的基本过程，并最终改善治疗和患者结果。