Treating Multiple Myeloma by Targeting the NF-Kappa-B Pathway with Gadd45-Beta/MKK7 Inhibitors

使用 Gadd45-Beta/MKK7 抑制剂靶向 NF-Kappa-B 通路治疗多发性骨髓瘤

• 批准号: MR/L005069/1
• 负责人: Guido Franzoso
• 金额: $ 496.28万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL005069%2F1
• 关键词: Treating; Multiple; Myeloma; Targeting; NF

Professor Guido Franzoso and his colleagues at Imperial College London have discovered a new way of tackling multiple myeloma, an incurable cancer of the white blood cells, which are normally responsible for producing 'antibodies,' that attacks and destroys bone, which could offer a cure for this disease. The treatments that currently exist for multiple myeloma have severe side effects that limit the doses that can be given to patients. The most recent treatment, bortezomib (Velcade), cannot completely destroy the cancer, allowing some of the cancer cells to escape this treatment and so, whilst the disease can be temporarily stabilised, relapse is unfortunately inevitable. Because of an increased number of antibody-producing white blood cells, patients generally have high levels of a single type of antibody called 'M-protein' in their blood and/or urine. These patients often also have reduced blood cell counts and decreased amounts of normal antibodies, which compromises their body's immune defenses against infection. As a result of these and other complications, most of the 110,000 people diagnosed each year with the disease in the US, Europe and Japan will die within about five years of diagnosis. This blood borne cancer cannot be treated using radiotherapy or surgery and so the options are restricted to chemotherapy or bone marrow transplant.Prof. Franzoso's team discovered a new protein, called Gadd45-Beta, which forms one half of a crucial signalling point within cells. An enzyme called MKK7 controls traffic through a second signalling pathway (JNK) that forms the other half of this focal signalling point. When bound together, the two Gadd45-Beta and MKK7 proteins stop the signals that tell the cancerous cells to activate a form of cellular suicide known to specialists as 'apoptosis', thus allowing them to multiply uncontrollably.The team has since developed a novel compound molecule, DTP3, which specifically disrupts the relationship and interaction between Gadd45-Beta and MKK7, and in so doing kills the cancerous cells effectively but, perhaps most importantly, completely lacks toxicity to the normal cells. This unique property makes DTP3 an exciting starting point in the search for a new effective drug therapy against multiple myeloma.The goal of the research team is now to progress DTP3 to an early stage clinical study in patients suffering from multiple myeloma in order to test the drug in man and ultimately develop an effective therapy with no toxicity, alongside a diagnostic test, for multiple myeloma and potentially other cancers where the Gadd45-Beta and MKK7 proteins are responsible for keeping the tumour cells alive.

伦敦帝国理工学院的Guido Franzoso教授和他的同事们发现了一种治疗多发性骨髓瘤的新方法，多发性骨髓瘤是一种无法治愈的白色血细胞癌症，通常负责产生“抗体”，攻击和破坏骨骼，这可能为这种疾病提供治疗方法。目前存在的多发性骨髓瘤治疗方法具有严重的副作用，限制了患者的剂量。最新的治疗方法硼替佐米（Velcade）不能完全摧毁癌症，使一些癌细胞逃脱这种治疗，因此，虽然疾病可以暂时稳定，但复发是不可避免的。由于产生抗体的白色血细胞数量增加，患者的血液和/或尿液中通常含有高水平的单一类型的抗体，称为“M蛋白”。这些患者通常也有减少的血细胞计数和正常抗体的数量减少，这损害了他们的身体对感染的免疫防御。由于这些和其他并发症，美国，欧洲和日本每年诊断出的110，000人中的大多数人将在诊断后约五年内死亡。这种血液传播的癌症无法通过放射治疗或手术治疗，因此选择仅限于化疗或骨髓移植。Franzoso教授的团队发现了一种新的蛋白质，称为Gadd 45-Beta，它形成了细胞内关键信号点的一半。一种名为MKK 7的酶通过第二条信号通路（JNK）控制交通，该信号通路形成了这个焦点信号点的另一半。当两种Gadd 45-Beta和MKK 7蛋白结合在一起时，它们会阻止癌细胞激活一种被专家称为“细胞自杀”的细胞自杀形式的信号，从而使它们不受控制地繁殖。该团队后来开发了一种新的化合物分子DTP 3，它专门破坏Gadd 45-Beta和MKK 7之间的关系和相互作用，并且这样做有效地杀死癌细胞，但可能最重要的是，对正常细胞完全没有毒性。这种独特的性质使DTP 3成为寻找新的有效治疗多发性骨髓瘤的药物的一个令人兴奋的起点。研究小组的目标是将DTP 3进展到多发性骨髓瘤患者的早期临床研究，以便在人体中测试药物，并最终开发出一种有效的无毒性治疗方法，同时进行诊断测试，对于多发性骨髓瘤和潜在的其他癌症，其中Gadd 45-Beta和MKK 7蛋白负责保持肿瘤细胞存活。

项目成果

Turning an old GADDget into a troublemaker.

• DOI: 10.1038/s41418-018-0087-6
• 发表时间: 2018-03
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Capece D;D'Andrea D;Verzella D;Tornatore L;Begalli F;Bennett J;Zazzeroni F;Franzoso G
• 通讯作者: Franzoso G

Enhanced Triacylglycerol (TAG) catabolism by CES1/TGH promotes aggressvie colorectal carcinoma

CES1/TGH 增强的三酰甘油 (TAG) 分解代谢促进侵袭性结直肠癌

• 发表时间: 2021
• 期刊: J Clin Invest
• 影响因子: 15.9
• 作者: Capece D