Cellular and Molecular Oncology

This first lecture gave an overview of the history of our knowledge of tumors, from the role played by microscopy in defining them, to genomics and experimental cancer in animals. I then stressed the importance of the epidemiological work carried out from the 1950s onwards in identifying the risk factors for cancers prevalent in humans. The major role played by viral infections and tobacco intoxication was highlighted. I then presented the contributions of virology, in particular 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 master regulator of proliferation), which are often bound 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 is largely based on the acquisition of gene mutations (activating or inactivating) throughout an individual's life. The transition from a normal cell to a transformed cell requires close cooperation between oncogenes and anti-oncogenes. Carcinogenesis is therefore a multi-stage process in which a cell progressively acquires lesions in its genetic heritage. In most cases, these lesions have no consequences. Sometimes, they lead to the cell's death. More rarely, they confer a selective advantage in survival or proliferation. This model of progressively acquired genetic disease of the cell explains the late incidence of spontaneous tumors in humans.

I then sought to shed light on the reversibility of the transformed state, as well as on the possibility of targeting proteins to ensure the permanence of this state. Using the leukemia model, which I've been studying for over 25 years, I wanted to show that the destruction of the master protein of cellular transformation (the PML/RARA fusion) made it possible to obtain a cure for this disease through the combination of a hormone, retinoic acid, and a pro-oxidant toxicant, arsenic, both of which bind to the PML/RARA protein. Binding of these drugs to the PML/RARA protein leads to its degradation, activation of the p53 protein and rapid disappearance of the leukemic clone. Retinoic acid and arsenic are the first targeted therapies capable of inducing definitive cures by eliminating the molecular engine of the disease. I then presented an overview of the field, focusing in particular on the power of genome analysis approaches, which today enable an individual description of human tumors. These technologies could lead to better targeting of the genetic abnormalities responsible for cell transformation, with potentially significant clinical benefits.