The College de France in Oxford : ‘Constructing a biology of cancer cure’ by Hughes de Thé

On the occasion of the second Collège de France - Maison Française d'Oxford - Pembroke College lecture, Professor Hugues de Thé will be giving a talk on ‘Constructing a biology of cancer cure’

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Together with clinicians at St. Louis Hospital and a Chinese team, we have conducted a detailed biological analysis of the biological basis of the effects of retinoic acid and arsenic in a specific form of leukemia, Acute Promyelocytic Leukemia (APL). We first discovered the driving force behind leukemic transformation, the PML/RARA oncoprotein. We then demonstrated that the two active drugs are able to bind directly to this protein and initiate its degradation. Retinoic acid and arsenic are therefore targeted therapies, even if they were initially discovered by chance. The disappearance of the PML/RARA protein, the driving initiator of leukemogenesis, is accompanied by the reformation of

specific domains of the cell nucleus: PML bodies. By controlling senescence and cell death, these domains are required for APL cure. Our work has also enabled us to demonstrate a remarkable synergies between these two agents, first in pre-clinical models, then in patients. Today, the combination of retinoic acid and arsenic definitively cures the vast majority of APL patients, without genotoxic chemotherapy. The few patients who relapse often present mutations abolishing the binding of retinoic acid or arsenic to PML or PML/RARA, thus validating our experimental models. Our work demonstrates that an intimate understanding of the molecular and cellular mechanisms involved in therapeutic response enables rational optimization of the too often empirical use of anticancer drugs.