Cells undergo a meticulous process of growth and migration to form tissues and organs. This process is regulated by various intracellular pathways, including the PTEN/PI3K axis, which ensures balanced chemical reactions. Mutations in the PTEN gene can lead to PI3K overactivation, resulting in cancer types such as breast and prostate cancers and disorders grouped under PTEN Hamartoma Tumor Syndrome (PHTS). These conditions are characterized by vascular malformations in half of the patients, causing severe pain and swelling. Current treatments like surgery or embolization may not always be feasible due to lesion localization. Recent research led by Dr. Mariona Graupera has identified "uniparental disomy" as the genetic cause behind PHTS-related vascular malformations. Using this discovery, the team developed the first mouse model for these malformations.

The study further explored the efficacy of drugs targeting PI3K's downstream effects, revealing that rapamycin and capivasertib inhibitors significantly reduce vascular growth, whereas alpelisib showed no substantial benefit. The off-label use of rapamycin on two PHTS patients demonstrated reduced vascular overgrowth and alleviated associated pain. These findings pave the way for early diagnosis and improved quality of life for PHTS patients, emphasizing the potential for clinical intervention before cancer development.

Genetic Insights into Vascular Malformations

Research conducted at the Josep Carreras Institute unveiled a critical genetic mechanism known as "uniparental disomy," where one functional copy of the PTEN gene is replaced with a non-functional counterpart in endothelial cells. This mechanism explains the onset of vascular malformations observed in PHTS patients. Through extensive biopsy analysis and experiments involving patient-derived endothelial cells, scientists have established a clear link between this genetic anomaly and subsequent vascular abnormalities.

In-depth studies using mouse models further substantiate the role of uniparental disomy in triggering vascular malformations. By replicating the genetic alteration in mice, researchers were able to observe and document its impact on the vasculature. This groundbreaking discovery not only enhances our understanding of PHTS but also opens avenues for developing preclinical models crucial for testing molecular therapies. The ability to replicate the disease in animal models provides invaluable insights into disease progression and potential therapeutic interventions.

Potential Therapeutic Breakthroughs

Building upon the genetic discoveries, researchers tested various anticancer drugs to counteract PI3K overactivation. Drugs targeting downstream effectors of PI3K, specifically rapamycin and capivasertib, demonstrated significant reductions in vascular growth. In contrast, direct inhibition of PI3K using alpelisib proved ineffective. These findings suggest that focusing on downstream pathways might offer more promising therapeutic outcomes compared to directly inhibiting PI3K.

Translating these laboratory findings into clinical practice, the team administered rapamycin off-label to two PHTS patients. The results were encouraging, showcasing reduced vascular overgrowth and diminished pain associated with lesions. This proof-of-concept underscores the potential of rapamycin as an effective treatment option for PHTS patients suffering from vascular malformations. Furthermore, the ability to diagnose PHTS through pediatric manifestations offers a unique opportunity for early intervention, potentially improving patient survival rates and overall quality of life. With continued research and funding support, these advancements hold great promise for transforming PHTS management and treatment protocols in the future.