Chemotherapy, alongside radiotherapy and surgery remains the mainstay of treatment for many cancers. However as our understanding of the biology of malignancy improves targeted therapies are being developed, which need to be integrated with existing standard chemotherapeutics. This thesis discusses three studies that aim to address this challenge. In the first part of this thesis, the activity of lomeguatrib, a novel agent that acts as a pseudosubstrate for the DNA-repair protein MGMT, was investigated in a range of solid tumours. Following a single administration, it was found to deplete MGMT in primary CNS, colorectal and prostate cancers. The lomeguatrib dose required to achieve this was independent of pre-treatment MGMT expression in these tumour types. MGMT expression appears to correlate with sensitivity to irinotecan, a standard treatment for metastatic colorectal cancer. Combination treatment with lomeguatrib and irinotecan was investigated in patients with metastatic colorectal cancer. Treatment with this couplet was tolerable, no pharmacokinetic drug interactions were seen and complete MGMT depletion was observed. In this heavily pre-treated group of patients, there was no increase in efficacy with treatment with the couplet over irinotecan alone. The latter part of the thesis describes an ongoing early phase trial investigating combination treatment with decitabine, a hypomethylating agent and standard ECF chemotherapy in patients with advanced oesophagogastric cancer. The maximum tolerated dose of decitabine in this combination was established, the main toxicity myelosuppression was manageable. Preliminary tumour DNA pyrosequencing results confirmed changes in methylation of the MAGE 1A gene in tumour tissue associated with immunohistochemical changes in protein product expression of a number of genes following decitabine treatment. These studies have described early phase work for two very different targeted treatment approaches that may be used alongside standard chemotherapy. Clinical studies to explore both of these further are planned
