News from the lab – December 2020

Dear GoPI3Ks/CLOVES community, 

When Mandy Sellars approached me about a contribution to this year’s GoPI3Ks newsletter, I could not help asking myself the same old question: “Is this year ALREADY over?”

As usual, this question triggered substantial reflections. It is hard to believe that it has been a bit over a year already since I moved to Bart Vanhaesebroeck’s group at University College London’s Cancer Institute, with plans to study the complexity of “the PI3K radio”. This research will hopefully form the basis for improved disease understanding and potentially also for better treatment solutions, not only in the context of PIK3CA-related overgrowth syndrome (PROS; includes CLOVES) but also for other diseases such as cancer. So to recap, among the key questions that I am interested in studying, and the ones that I think will resonate with many of you, are: 

  1. Do different cells or tissues in the body respond differently to the same PIK3CA mutation? (for example, some of you may share the same PIK3CA mutation, e.g. H1047R, yet suffer from strikingly different symptoms due to differences in the affected cells/tissues)
  1. What cell-based mechanisms explain differences in disease severity with different PIK3CA mutations? (for example, two individuals may both suffer from vascular malformations but due to differences in the type of PIK3CA mutation, one case may be milder than the other – why is that?)
  1. Not all cells in an affected tissue carry a PIK3CA mutation, so what is the contribution of the ‘normal bystanders’ to the overall disease?
  1. Finally, can the above knowledge be used to identify pharmacological therapies that are more suitable for different types of PROS?

I always try to be mindful of the fact that not everyone will be familiar with some of the above academic jargon, so let me include a short explainer when it comes to some key terms. PIK3CA is the name of a stretch of DNA which provides our cells with the code for producing an enzyme that is critical for growth and survival. PROS is characterised by the presence of changes, or mutations, in this stretch of DNA, thereby resulting in a more active enzyme. The higher activity of the mutant enzyme makes it hard for an affected cell to turn ‘growth’ programmes off. Due to differences in the timing during development when a mutation is acquired, the exact cells that are affected and the type of PIK3CA mutation, people with PROS can suffer from vastly different symptoms. 

Some good news from 2020

The end of a year is always a good time to take stock – of what has happened and what is to happen. Although 2020 was not exactly a year full of good news, I am pleased to let you know that I was successful in my application for a research fellowship from the Wellcome Trust. This means that my salary and research funding for PROS/cancer-related work is secured for another 4 years. Among others, I am incredibly grateful for the support of my previous (Prof Robert Semple) and current (Prof Bart Vanhaesebroeck) mentors, without whom this achievement would not have been possible.

I also received a substantial research contribution from the CLOVES Community – thank you for that! I have invested the money in making a novel cell-based model (a research tool) that is of relevance to understanding PROS, and one that will be critical for studying the key questions listed above. More specifically, I have tasked some of the leading gene engineering companies, Synthego and GeneWiz, with the generation of this cell model and additional components for its downstream research use. These are by no means trivial tasks, so my wish this Christmas is to hear back from both Synthego and GeneWiz with successful news regarding this project. More on this in a year’s time when we know whether I have been successful with this task or not!

There is also good news when it comes to immediate treatment prospects for PROS – as some of you may know, a worldwide clinical trial of Alpelisib in PROS is in the pipeline. This will allow an accurate picture to be obtained of which parts of PROS Alpelisib is most beneficial for, and of which ages of patients are best to treat, and, critically, how significant side effects are. Novartis, the company who makes Alpelisib, is in advanced stages of finalising such a trial, spread across several countries, and projected to last up to 5 years.  The US arm of the study is already registered (, and other countries are expected to follow soon. 

Upwards and onwards into 2021

The year 2020 has certainly been a tough one for many, and I am sincerely hoping that you are all well and safe. Despite its bleak nature, the above goes to show that there are always glimmers of hope for all of us. For me, research comes with many ups and many more downs. In fact, it is almost universally true that as a researcher, you spend most of your time figuring out why an experiment is not working or how it can be improved. The more technically complex the experiment (most of them are nowadays!), the higher the risk of failure. Yet, on days when I feel particularly defeated by yet another hurdle, I keep reminding myself that I am not just doing this for me – I am doing it because it may one day have a positive impact on your lives, and that keeps me going. So thank you all for your continued support and faith in my work. It is hugely appreciated.

Happy Holidays to you and yours!

Dr Ralitsa Madsen (UCL Cancer Institute, London, UK)