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

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细胞癌症，白细胞通常负责产生攻击和破坏骨骼的“抗体”，这可能是治疗多发性骨髓瘤的一种方法。目前多发性骨髓瘤的治疗方法有严重的副作用，限制了患者的剂量。最近的治疗，硼替佐米（Velcade），不能完全摧毁癌症，允许一些癌细胞逃避治疗，因此，虽然疾病可以暂时稳定，但不幸的是复发是不可避免的。由于产生抗体的白细胞数量增加，患者的血液和/或尿液中通常含有高水平的一种称为m蛋白的抗体。这些患者通常也有血细胞计数减少和正常抗体数量减少，这损害了他们身体对感染的免疫防御。由于这些和其他并发症，在美国、欧洲和日本，每年有11万人被诊断出患有这种疾病，其中大多数人将在确诊后的五年内死亡。这种血源性癌症不能用放疗或手术治疗，因此只能选择化疗或骨髓移植。Franzoso的团队发现了一种名为Gadd45-Beta的新蛋白质，它构成了细胞内一个关键信号点的一半。一种叫做MKK7的酶通过第二个信号通路（JNK）控制交通，JNK形成了这个焦点信号点的另一半。当两种gadd45 - β和MKK7蛋白结合在一起时，会阻止告诉癌细胞激活一种被专家称为“凋亡”的细胞自杀形式的信号，从而使它们无法控制地繁殖。该团队已经开发出一种新的化合物分子DTP3，它可以破坏Gadd45-Beta和MKK7之间的关系和相互作用，这样做可以有效地杀死癌细胞，但也许最重要的是，对正常细胞完全没有毒性。这种独特的性质使DTP3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。该研究团队目前的目标是将DTP3推进到多发性骨髓瘤患者的早期临床研究，以便在人体中测试该药物，并最终开发出一种无毒性的有效疗法，同时进行诊断测试，用于多发性骨髓瘤和潜在的其他癌症，其中gadd45 - β和MKK7蛋白负责保持肿瘤细胞的存活。

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.