Development of Gadd45b-Targeting Agents for Multiple Myeloma Therapy

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，这可能会为这种疾病提供治疗方法。相比之下，现有药物有严重的副作用，限制了可以给予的剂量。最新的治疗方法Bortezomib(VELCADE)无法杀死所有癌症，使一些癌细胞逃脱，虽然疾病可以暂时稳定，但复发是不可避免的。因此，在美国、欧洲和日本，每年被诊断患有这种疾病的11万人中，大多数人将在大约3-5年后死亡。这种血液传播的癌症不能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。我们发现了一种名为Gadd45b的新蛋白质，它构成了细胞之间关键分子联系的一半。一种名为MKK7的酶控制第二信号通路(JNK)的流量，这两个分子结合在一起，阻止告诉正常骨髓细胞死亡的信号，使它们无法控制地繁殖。我们设计了阻止这两种蛋白质相互结合的小分子。与正常骨髓相比，多发性骨髓瘤癌细胞含有高水平的Gadd45b，我们已经证明，我们可以在实验室通过阻止Gadd45b与其伴侣MKK7结合来杀死人类骨髓瘤细胞。我们已经证明，这些蛋白质不会影响正常细胞，使它们成为寻找新药物疗法的有希望的起点。下一步将是找出这些分子在癌症模型中的行为，并利用这些信息创造第二代改进的分子。在这项研究结束时，我们的目标是创造一种可以在一到两年内给患者服用的化合物。这种疗法不仅可以稳定病情，还可能治愈多发性骨髓瘤。该团队在制药行业拥有广泛的成功药物发现和开发经验，并将利用帝国理工学院？S广泛的生物、化学和临床设施开发多肽分子。

Professor Guido Franzoso and his colleagues at Imperial College have discovered a new way of tackling multiple myeloma, a cancer of the bone marrow, which could offer a cure for this disease. In contrast, existing drugs have severe side effects that limit the doses that can be given. The most recent treatment, bortezomib (Velcade) cannot kill all of the cancer, allowing some of the cancer cells to escape and, whilst the disease can be temporarily stabilised, relapse is inevitable. As a result, most of the 110,000 people diagnosed each year with the disease in US, Europe and Japan will die about 3-5 years later. This blood borne cancer cannot be treated using radiotherapy or surgery and so the options are restricted to chemotherapy or bone marrow transplant. We have discovered a new protein, called Gadd45b, which forms one half of a crucial molecular link between cells. An enzyme called MKK7 controls traffic in a second signalling pathway (JNK) and, bound together, these two molecules stop the signals that tell normal bone marrow cells to die, allowing them to multiply uncontrollably. We have designed small molecules that prevent the two proteins from binding to one another. Multiple myeloma cancer cells contain high levels of Gadd45b, compared to normal bone marrow, and we have already shown that we can kill human myeloma cells in the laboratory by preventing Gadd45b from binding to its partner, MKK7. We have shown that these proteins don?t affect normal cells, making them promising starting points in the search for a new drug therapy. The next steps will be to find out how these molecules behave in models of cancer, and use this information to create a second generation of improved molecules. At the end of this study we aim to create a compound that can be given to patients within a year or two. This treatment will not only stabilise the disease, but may actually offer a cure for multiple myeloma. The team has wide experience of successful drug discovery and development within the pharmaceutical industry and will develop the peptide molecules using Imperial College?s extensive biological, chemical and clinical facilities.