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From ‘white noise’ to music: repairing the broken PI3K radio - Dr. Ralitsa Madsen

December 7, 2019

Dear GoPI3K/CLOVES community: 

Somehow – and somewhat too fast for my taste – another year has passed, and the time has once again come for my annual contribution to the GoPI3K Christmas Newsletter. This is also the first time that this Newsletter will be shared with the CLOVES community in the U.S., and I hope it will be informative for all parties.  To start with some generic news, I have now joined the research group of Prof Bart Vanhaesebroeck at University College London. This is a natural move for someone at my career stage – transitioning from being a PhD student to becoming a so-called postdoc. That said, I still retain a close connection to Prof Robert Semple, and my future work will  almost certainly feature his input in one way or another.

A few words about Prof Bart Vanhaesebroeck and his group before I get into the details of my upcoming research and how it relates to PROS. Bart is a world-renowned expert in cancer research, with a specific focus on the so-called PI3K signalling pathway. This is the molecular circuit that becomes dysfunctional in PROS and in a lot of human cancers due to a ‘spelling mistake’ (or mutation) in a gene known as PIK3CA. By genetically engineering laboratory mice, Bart’s group has contributed several key disease model systems of both cancer and PROS. With a strong focus on drug development, the group’s work has also resulted in the development of pharmacological therapies for specific cancers.

By joining Bart’s group, I am in the fortunate position to tap into the wide range of resources and knowledge that his team has established over the years – an ideal combination for my 4-year PI3K research vision. I am personally very excited at this opportunity because it will allow me to pursue novel research questions, some of which are of particular relevance to PROS. Indeed, I remain firmly committed to understanding molecular aspects of PROS diseases; only when we understand these mechanisms can we be certain that effective therapies will eventually become the norm for all patients. 

 

From ‘white noise’ to music: repairing the broken PI3K radio

While typing away on my computer on a flight back home earlier this year, the person sitting next to me got interested in my work and asked about my research area (the disease terms on my screen gave my discipline away!). As it happened, I ended up telling him about my future research vision instead. To explain it in lay terms, I showed him the picture of my so-called ‘PI3K radio’. I told him that there are individuals in whom the radio doesn’t play music – instead, all you hear is ‘white’ noise. In other words, the radio is out of tune. This analogy can be used to describe the state of cells in a patient with a PIK3CA flaw. A functional PIK3CA is required for the cells to execute their normal functions, yet in PROS patients, a defective PIK3CA is bringing the system out of balance. Similar to a broken radio, the cells are out of tune with their environment and misinterpret the signals they receive. For example, whereas a normal cell would stop growing in the absence of nutrients, cells with defective PIK3CA grow unabated, giving rise to the characteristic overgrowth in individuals with PROS.

So far so good. I then told my neighbour that many pharmaceutical companies and academics are keen on fixing the broken radio, especially because of its importance in cancer. What has their ‘fixing’ strategy been so far? To simply switch PIK3CA off. BYL719 or Alpelisib, which many of you would know about, works like that. It enters the cell and switches both its normal and its defective PIK3CA off. Supported by recent clinical reports, this approach is not necessarily wrong – at least when it comes to PROS, it has proven effective in a small number of patients treated on a compassionate basis. However, we also know that in cancer, simply switching PIK3CA off does not confer long-term disease stabilisation, i.e. it is not a cure. In PROS, a question that remains unanswered is whether simply switching PIK3CA off will be sufficient to reverse developmental abnormalities such vascular malformations which affect a substantial proportion of patients. This, I said to my neighbour, is where my future research comes in.

To me, simply switching PIK3CA off corresponds to turning the radio off – while the annoying ‘white noise’ may have stopped, the radio still does not play the music I want to hear. To learn how to fix it, I propose to take a different approach inspired by the question: what would an engineer do? Rather than studying each component of the radio separately, as most conventional biologists do when they study cells, the engineer would study the system of components and how they are wired to one another. Analogously, my research on PI3K in the next four years will focus on the system – all the different cell components that are linked to PIK3CA – and how it functions as a unit. To achieve this, I will collaborate with mathematicians and computational scientists who will teach me how to analyse new types of experimental data that can be used to predict optimal therapeutic strategies for cells with PIK3CA defects.

This is not a trivial task. Biological systems feature a bewildering complexity. Although many PROS patients share the same type of PIK3CA defect, they do not necessarily share its location. Different tissues – and therefore different cells – may be affected. Each one of these represents a slightly different radio design, with slightly different wiring. Each one will play a slightly different tune. Eventually, I want to understand them all to be able to predict optimal treatment strategies that are tailored to a patient’s specific disease. For a start, however, I will have to restrict myself to two particular cell types – one of which corresponds to the cells that line the blood vessels in PROS patients with vascular malformations.

Even with two cell types to study, this research will take time and cost a lot of money. Thus, my Christmas wish this year is to obtain the funding that I am currently applying for to support my work. Beyond money, the remaining success ingredients are patience and perseverance. With those in place, I am confident that the systems approach will eventually get us to a point where each PROS individual’s PIK3CA radio plays the right tune again. 

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

 

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