Grant: CIHR Fellowship

Overgrowth syndromes consist of a group of diseases characterized by excessive growth of certain parts of the body and a variety of anatomical deformities. As an example, Joseph Merrick (1862-1890), also known as "The Elephant Man", is thought to have suffered from a severe form of this disease. Because of his deformities, he was abandoned by his family at a young age and exploited as a circus freak during his early twenties. He died of asphyxia at age 27 due to compressive deformities in the neck region. We now know that overgrowth syndromes are caused by genetic defects that arise after conception, starting at the embryo stage. One of the most common defects occurs in a protein called PIK3CA that controls the growth and proliferation of cells. The body parts affected by this defect eventually increase in size, which leads to large and painful masses that can compress any adjacent organ in the body . PIK3CA-related overgrowth syndromes (PROS) also often leads to premature death. Recently, a PIK3CA blocker has been used by Dr. G. Canaud (Université de Paris) to treat PROS and led to spectacular reductions in the size of masses. For unknown reasons, however, this blocker did not completely reverse the overgrowths in certain organs. This proposal is based on these premises and aims to understand why there can be resistance to the blocker. This work will be tackled through the characterization of animal models and clinical samples in which the PIK3CA protein is either overactive, normal or inhibited. The project should also help identify other proteins and markers useful for PROS diagnosis and treatment. Once the cause of the resistance to PIK3CA blockade is elucidated, it will become possible to treat PROS with new approaches in order to reach maximal reversion of the overgrowth process. As a result, affected patients will experience further improvement in their quality of life and life expectancy.