Principles of chemotherapy

Systemic cancer treatment stems initially from empirically discovered DNA synthesis inhibitors, which either deplete the cell of nucleotides, induce cross-link, or cause DNA single and double strand breaks or impair the cellular machinery of DNA repair, using mechanistically diverse drugs. A period of enlightenment followed, with anticancer drug development driven by an increased understanding of enzymes and pathways involved in cell signalling, control of angiogenesis, and epigenetics. This provided a parallel path towards precision cancer medicine where specific drugs can be targeted to patients with particular mutations. These include point mutations in RAS, which are used to exclude colorectal cancer patients from being treated with epidermal growth factor inhibitors; chromosomal translocations encoding fusion proteins which are cancer specific and serve as novel drug targets (e.g. BCR/ABL and imatinib, or EML4-ALK fusion oncogene and crizotinib). More recently, there has been a reanimation of immune approaches to cancer therapy with the clinical introduction of immune checkpoint inhibitors, designer T cells, and patient-specific antitumour vaccines. What next? It may be that next-generation sequencing provides an endless stream of so-called actionable mutations that permits tailored application of mutation-specific drugs, but so far there is little evidence of clinical benefit from such therapies.