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Activation of PI3K signalling in the pathogenesis of Vascular Anomalies

Periodic Reporting for period 1 - PI3K-VAs (Activation of PI3K signalling in the pathogenesis of Vascular Anomalies)

Reporting period: 2018-09-01 to 2020-08-31

Vascular malformations are rare diseases that consist in an overgrowth of the blood and lymphatic vessels. These are congenital diseases that are present when the patient is born, thus they occur during embryonic development. Vascular malformations grow with the patient and they are very painful and disfiguring, they cause bleedings, infections and can invade and obstruct vital organs. Recently, we discovered new causing mutations leading to venous malformations, the most common type of vascular malformations. These mutations are similar to those found in epithelial tumours such as breast and colon; however, the specific biology and impact of these mutations in vascular malformations were unknown. Also, the therapeutic effect of targeted therapies that can be repurposed from oncology was underexplored due to the lack of biological insights and preclinical tools for these diseases. With this project we aimed to i) understand the biological mechanisms that lead to the pathogenesis of these diseases, ii) generate state of the art preclinical tools, and iii) assess a spectrum of targeted therapies for these rare diseases. Findings and studies from this project have impacted the way patients with vascular malformations are managed since we have translated our results into the clinic through our clinical partners and this has had an impact on their genetic and molecular diagnosis. Also, our preclinical tools have allowed pharma companies to test molecular inhibitors specifically for these rare diseases, helping in the process towards clinical trials.
During this project we have analysed biopsies from vascular malformations and we have found that the mutations causing the disease are present in the endothelial cells, which are the main cells present in vessels. However, these cells are present in a very small proportion in biopsies from these lesions which makes the genetic diagnose very challenging. To overcome this limitation, we have developed new tools and approaches that have been translated into the clinic. This includes state of the art ultra-sensitive next generation sequencing technology. We have also created rapid and very robust in vitro and in vivo tools to understand this disease. With them, we analysed the impact of causing mutations specifically in endothelial cells and identify molecular and cellular mechanisms underlying the pathogenesis. This allowed us to assess the therapeutic effects of drugs in blocking and reversing the disease-driven mechanisms. Our preclinical studies involved biochemistry, cell signalling and high content imaging techniques to test inhibitors repurposed from oncology studies.
Our fundamental results have been disseminated to the scientific community through national and international meetings in the field of vascular anomalies, angiogenesis and cellular signalling. Also, due to the translational nature of our findings we have been very active in dissemination of our results to the clinical community through meetings in the fields of vascular anomalies and dermatology and through regular meetings with a multidisciplinary team of clinicians managing these patients (dermatologists, oncologists, radiologists and surgeons). Importantly, we have also set up collaborations with two Spanish patients’ associations having annual meetings with members and their families. To engage the general public into the importance of science for our community I have been a Marie Skłodowska-Curie ambassador in talks to high school students, activities for children and to make visible women in science. I have also used social media to disseminate our key scientific findings as well as those from the scientific community.
This project has generated novel preclinical systems that are key in the development and implementation of targeted and personalised therapies for these rare diseases. Our unique resources generated from this project are now being evaluated for industrial exploitation. As a proof of context for the exploitation of these tools, we have set up research collaborations with the pharma industry to assess their drugs in our preclinical systems that might help in the process towards clinical trials. This will ultimately have a beneficial impact for patients in the in the coming years.
Proliferating endothelial cells in a vascular malformation