Development of peptide-drug conjugates for the treatment of Chronic Myelomonocytic Leukaemia (CMML)

慢性髓细胞白血病（CMML）是一种血癌，一般没有有效的治疗方法。对于大多数被诊断为CMML的人来说，预后很差，50%的患者在诊断后15-20个月内死亡。CMML的化疗方法经常失败，因为相对于患者身体的其他部分，对癌细胞缺乏选择性，或者对骨髓中导致疾病复发的癌细胞缺乏活性。我们正在寻求通过开发一种新的药物来解决这一不足，这种药物可以选择性地靶向并通过患者的身体杀死癌细胞，而对健康细胞类型几乎没有影响。我们将通过将一种剧毒化合物附着在一种蛋白质上来实现这一目标，这种蛋白质只被CMML患者癌变的细胞类型所吸收。我们已经证明，这些药物的原型可以在试管中选择性地靶向和杀死CMML细胞，并且在动物实验中保持这种活性和选择性，这是模拟治疗CMML患者的复杂需求所必需的。在这个项目中，我们将进行进一步的研究，以尽可能确保这些化合物对治疗CMML有用，同时也开发这些原型，以确保它们具有在患者身上测试所需的所有特性。如果成功，这将为我们提供所需的所有信息，使这些药物进行最终毒性测试，然后在CMML患者中进行临床试验。

Chronic Myelomonocytic Leukaemia (CMML) is a type of blood cancer for which is no generally effective treatment. For the majority of people diagnosed with CMML the prognosis is dismal, with 50% of patients dying within 15-20 months of diagnosis.Chemotherapy approaches in CMML frequently fail due to a lack of selectivity for the cancerous cells relative to the rest of the patient's body, or lack of activity against the cancerous cells in the bone marrow that cause the disease to recur. We are seeking to address this shortfall by developing a new class of drug that selectively targets and kills the cancerous cells through the patient's body, with little or no impact on healthy cell types. We will achieve this by attaching a highly toxic compound to a protein that is taken up only by the type of cells that have become cancerous in patients with CMML.We have demonstrated that a prototype of these drugs can selectively target and kill CMML cells in a test tube and that this activity and selectivity is maintained in animal experiments, which are needed to model the complex requirements of treating a patient with CMML.In this project we will conduct further studies to make as sure as possible that these compounds will be useful for treating CMML, whist also developing these prototypes to ensure they have all the required properties for testing in patients. If successful this will give us all the information we need to take one of these drugs into final toxicity tests and then clinical trials in CMML patients.