Oncology: from empiricism to integrated biology

This first lecture provided an overview of the history of our understanding of tumours, from the role played by microscopy in their characterisation, through to genomics and experimental cancer research in animals. I then emphasised the importance of the epidemiological studies conducted from the 1950s onwards in identifying the risk factors for the most common cancers in humans. The major role of viral infections and tobacco-related toxicity was then highlighted. I then outlined the contributions of virology, particularly those relating to retroviruses, to the identification of the first cancer genes (oncogenes). Studies of viruses with a DNA genome have led to the discovery of anti-oncogenes (in particular p53, the master gene of the stress response, and RB, the main regulator of proliferation), which are often linked to and inactivated by viral proteins. These anti-oncogenes can also be inactivated by mutations present from conception (germline mutations) in rare familial forms of cancer.

Carcinogenesis relies largely on the acquisition of gene mutations (activating or inactivating) throughout an individual’s lifetime. The transition from a normal cell to a transformed cell requires close cooperation between oncogenes and tumour suppressor genes. Carcinogenesis is therefore a multi-stage process in which a cell gradually acquires lesions in its genetic material. In most cases, these changes have no consequences. They sometimes lead to cell death. More rarely, they confer a selective advantage in terms of survival or proliferation. This model of a progressively acquired genetic disease in the cell explains the delayed onset of spontaneous tumours in humans.

I then sought to shed light on the reversibility of the transformed state, as well as on the possibility of targeting the proteins responsible for maintaining this state. Using the model of leukaemia, which I have been studying for over 25 years, I sought to demonstrate that the destruction of the key protein involved in cellular transformation (the PML/RARA fusion) could lead to a cure for this disease through the combination of a hormone, retinoic acid, and a pro-oxidant toxin, arsenic, both of which bind to the PML/RARA protein. The binding of these drugs to the PML/RARA protein induces its degradation, the activation of the p53 protein and the rapid disappearance of the leukaemic clone. Retinoic acid and arsenic are the first targeted therapies capable of inducing definitive cures by eliminating the molecular driver of the disease. I then presented an overview of the field, focusing in particular on the power of genomic analysis approaches, which now enable the individual characterisation of human tumours. These technologies could lead to more precise targeting of the genetic abnormalities responsible for cellular transformation, a form of targeting from which we might expect significant clinical benefits.