PROS-VARIANT · PIK3CA-Related Overgrowth Spectrum: molecular mechanisms and preclinical modelling of PIK3CA VARIANTs
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
PIK3CA-Related Overgrowth Spectrum: molecular mechanisms and preclinical modelling of PIK3CA VARIANTs
The PIK3CA-related overgrowth spectrum (PROS) includes a group of rare congenital disorders that result in abnormal tissue growth in various parts of the body, such as the vasculature, fat, muscle, bone, brain, and skin. Patients with PROS can have a wide range of clinical manifestations depending on which tissues are affected; some may present as complex syndromes, while others may have isolated lesions like vascular malformations. These disorders arise from somatic mutations in the PIK3CA gene that occur during early development. The PIK3CA gene encodes the p110a protein (PI3Ka), a catalytic isoform of the PI3K responsible for generating the lipid PIP3 which serves as second messenger. The PI3Ka signaling pathway regulates essential cellular processes such as growth, survival, proliferation, and migration. In disease contexts, activating mutations in PIK3CA can occur throughout the entire gene leading to the overactivation of this signaling pathway. Individuals with PROS often face serious complications and life-threatening conditions, which require extensive surgeries and treatments like pulsed laser therapy and sclerotherapy. However, current treatments are frequently insufficient, leading to high rates of recurrence and worsening symptoms. Recently, the FDA approved alpelisib, a targeted medication for treating PROS, which has reduced tissue growth and pain in some patients; however, ohters do not respond well or experience significant side effects, causing them to stop treatment. This highlights the urgent need for a deeper understanding of the specific biological pathways involved in PROS, which can help improve patient care and lead to the development of more effective therapies that minimize side effects. Since PROS primarily affects children, better insight could allow for earlier interventions, reducing complications and improving long-term health outcomes. The main goals of our project were to gain insights into the physiological and molecular aspects of PROS by exploring key questions about when (the timing of mutation acquisition), where (the specific cell types involved), which (the types of PIK3CA mutation), and how (the mechanisms triggered by these mutations) these factors contributed to the development and severity of PROS. Our specific objectives included: (1) identifying the molecular and cellular changes caused by strong (H1047R) and weak (E726K) PIK3CA mutations and (2) studying how PROS develops over time and in different tissues using new mouse models.
Data: CORDIS, © European Union
Project objective
PIK3CA-related overgrowth spectrum (PROS) is a group of rare congenital disorders that manifest as complex syndromes with overgrowth of several tissues (vasculature, adipose and muscle tissues, bones, brain and skin among others) or as localized lesions such as vascular malformations. PROS is caused by somatic activating mutations in the PIK3CA gene that arise postzigotically during embryonic development. Patients suffer dramatic functional and life-threatening complications and typically require extensive mutilating surgery, pulsed laser, and/or sclerotherapy. However, these treatment strategies are insufficient, and patients commonly experience a high risk of recurrence and progression. This is in part a reflection of poor understanding of the underlying cellular and molecular mechanism of their onset and progression. In this proposal, I aim to gain physiological and molecular insight into PROS and address fundamental biological questions concerning when (timing), where (cell linage), who (PIK3CA variant) and how (triggered mechanism) activating PIK3CA variants contribute to the development and severity of PROS. I will address the following key objectives: 1) identify the specific molecular and cellular alterations triggered by strong (H1047R) and weak (E726K) activating PIK3CA variants and 2) characterize their spatiotemporal pathogenesis in PROS using novel mice models. To this end, a combination of in vitro and in vivo approaches, using novel genetically modified mice will be implemented in order to provide new mechanistic insight into the underlying disease pathology and give rise to new preclinical models to test therapeutic treatments. Achieving these goals will strongly contribute to my training as international expert in PI3K signaling, cell biology and congenital diseases, my experimental skillset, and my development towards a well-embedded and independent researcher within European academia.
Original text from CORDIS.
Participants
- FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS · BadalonaCoordinatorSpain
Links
Data: CORDIS, © European Union