Dissection and targeting of novel pathogenic mechanisms mediating PIK3CA-driven overgrowth

This proposal addresses a major need to increase understanding and improve treatment of a group of severe developmental diseases caused by activating mutations in the PIK3CA gene. These are collectively called the PIK3CA-related Overgrowth Spectrum (PROS), and they begin before birth. The PIK3CA gene controls cell and tissue growth, and when it is genetically activated, the rules that ensure orderly, co-ordinated tissue growth are broken. Unhealthy increased and disorganised growth ensues.

Mutations are found in only some cells and tissues, a situation called genetic mosaicism, and this produces patchy, asymmetric excess growth. This often severely affects blood vessel formation to produce major risks of blood clots, bleeding and infections that can be life threatening, while other functions (e.g. breathing, walking) are also commonly affected by increased tissue bulk.

PROS is incredibly variable despite the common underlying mechanism. Many affected patients wait years for specific diagnosis, if it is ever made, as PROS does not "belong" to any one medical or surgical speciality.

When PIK3CA mutations were found to cause these diverse diseases, new opportunities to treat them emerged. This is because the same PIK3CA mutations causing PROS are common in cancers. Although PROS causes cancer very rarely indeed, PIK3CA-targeting drugs developed for cancer have raised great hopes in PROS, with one drug recently licenced in the USA based on an uncontrolled registry study.

However while this has some benefits, these are partial, and side effects are frequent. Thus major need exists to improve medical treatment.

In the rush to test cancer drugs in PROS, major questions about how PIK3CA mutations cause the disease have not yet been unanswered, although these may hold the key to developing new, smarter treatment. The scientific and clinical complexity of PROS means that ambitious multimodal translational research is required to advance understanding. In this project a team of two clinician scientists and three fundamental scientists will combine expertise in clinical medicine, genetics, stem cell biology, animal disease modelling and sophisticated data analysis.

The proposal has been informed by working with a PROS patient advocacy group (clovessyndrome.org) that has funded key preliminary work. The project will use cutting edge single cell analysis of affected human tissue from PROS patients, combining this with the power of disease modelling in human pluripotent stem cells and zebrafish.

Findings from human tissue and the model systems will be combined and used to identify new mechanisms driving PROS that might be targeted. Time windows when the existing clinical drug has its greatest effect will be identified, and by studying why sensitivity is greatest in these windows, we will devise and test new ways to increase the sensitivity of mutation bearing but not healthy cells.

We envisage two potential new strategies: (1) to "trick" affected cells to enter a state more vulnerable to current inhibitors; and (2) to identify messages from affected cells that trigger healthy cells around them to grow too much. If these messages can be disrupted then this may produce a new line of attack to combat excess growth in PROS.

Outcomes of the study will include 1) identification of new strategies worth testing as PROS treatments; 2) fundamental insights into the way tissue growth is regulated that are relevant also for cancer, and 3) key lessons about the best ways to study other "mosaic" genetic diseases.