KFO 262: Tumour Metabolism as Modulator of Immune Response and Tumour Progression

KFO 262：肿瘤代谢作为免疫反应和肿瘤进展的调节剂

• 批准号: 190230491
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/190230491?language=en
• 关键词: KFO; 262; Tumour; Metabolism; Modulator

The Clinical Research Unit aims at analysing the altered metabolism of tumour cells and its impact on the body¿s immune system to identify specific therapeutic targets in metabolic pathways for the inhibition of tumour growth and reactivation of the immune system. Two of the seven funded projects investigate the role of increased glucose and glutamine metabolism in tumour and the resultant increased production and secretion of lactic acid. The aim is not only to elucidate how lactic acid inhibits the activity and infiltration of immune cells in tumours, but also to test novel therapeutic approaches to inhibiting the production of lactic acid in vitro and in vivo. Further, the impact of lactic acid on the secretion of protumourigenic factors and the regulation of natural killer cells by hepatic stellate cells will be investigated. Another metabolite of interest is 5'-methylthioadenosine (MTA), an intermediate of the methionine and polyamine metabolism. Its concentration is increased in many tumours due to a deficiency of 5'-methylthioadenosine phosphorylase (MTAP). Increased levels of MTA do not only inhibit the response to interferons, but also stimulate migration of cancer cells and suppress T-lymphocyte activity. Primary goals are to reduce the metastatic potential of cancer cells and to restore tumour specific T-cell function for an improved efficacy of cellular immune therapeutic approaches by administering small molecule inhibitors of the MTAP/MTA signalling pathway. Another project focusses on the heat shock protein Hsp90, which plays an essential role in stabilising proteins that regulate tumour metabolism and angiogenesis. The pharmacologic inhibition of Hsp90 represents a promising approach in tumour therapy and the planned studies on the impact of Hsp90 inhibitors on tumour metabolism will lay the foundation for their clinical application in the treatment of gastrointestinal and hepatic cancers. The remaining two projects will develop and apply sensitive analytical methods for the accurate determination of metabolite abundance and flux in cells and tissues as well as peptides and proteins that mediate tumour progression and immune escape as a result of tumour specific alterations in cell metabolism.

临床研究单位旨在分析肿瘤细胞的代谢改变及其对人体免疫系统的影响，以确定代谢途径中抑制肿瘤生长和重新激活免疫系统的特定治疗靶点。七个资助项目中的两个研究了葡萄糖和谷氨酰胺代谢增加在肿瘤中的作用，以及由此产生的乳酸生产和分泌增加。其目的不仅是阐明乳酸如何抑制肿瘤中免疫细胞的活性和浸润，而且还测试了体外和体内抑制乳酸产生的新治疗方法。此外，将研究乳酸对促肿瘤因子分泌的影响以及肝星状细胞对自然杀伤细胞的调节。另一种感兴趣的代谢物是5 '-甲硫基腺苷（MTA），甲硫氨酸和多胺代谢的中间体。由于缺乏5 '-甲硫腺苷磷酸化酶（MTAP），其浓度在许多肿瘤中增加。MTA水平的增加不仅抑制对干扰素的反应，而且刺激癌细胞的迁移并抑制T淋巴细胞活性。主要目标是通过施用MTAP/MTA信号传导途径的小分子抑制剂来降低癌细胞的转移潜力并恢复肿瘤特异性T细胞功能，以提高细胞免疫治疗方法的功效。另一个项目的重点是热休克蛋白Hsp 90，它在稳定调节肿瘤代谢和血管生成的蛋白质方面发挥着重要作用。Hsp 90的药理学抑制代表了肿瘤治疗的一种有前途的方法，并且计划研究Hsp 90抑制剂对肿瘤代谢的影响将为其在胃肠道和肝癌治疗中的临床应用奠定基础。其余两个项目将开发和应用灵敏的分析方法，用于准确测定细胞和组织中代谢物的丰度和通量，以及介导肿瘤进展和免疫逃逸的肽和蛋白质，这是肿瘤特异性细胞代谢改变的结果。