A study proves the effectiveness of anticarcinogenic drugs in the treatment of PTEN hamartoma tumor syndrome

The research team, led by Dr Mariona Graupera, from the Josep Carreras Leukaemia Research Institute, alongside Dr Sandra Castillo from the SJD Research Institute, as well as Dr Eulàlia Baselga, Head of the Dermatology Department at the SJD Barcelona Children's Hospital, have conducted a study to determine the genetic origins of vascular malformations in patients with PTEN hamartoma tumor syndrome (PHTS) and have identified a potential treatment.

What is PTEN hamartoma tumour syndrome (PHTS)?

PTEN hamartoma tumor syndrome is a rare genetic disease caused by mutations in the PTEN gene. This gene plays a key role in regulating cell growth, and mutations in the gene can cause uncontrolled cell division, leading to benign tumors (hamartomas) and an increased risk of cancer. This disease affects around 1 in every 200,000 people.

You can be diagnosed with PHTS at various stages of life. In some cases, the disease is detected in infancy, manifesting as symptoms such as macrocephaly or hamartoma growth, while other patients are diagnosed in adulthood with the appearance of neoplasms. A definitive diagnosis is rendered after a genetic screening to detect the mutation in the PTEN gene.

‘Early diagnosis, especially when vascular malformations are detected, could make subsequent treatment and monitoring of tumors and cancer much easier. In this study, three patients were diagnosed with PHTS after they were found to have a vascular malformation, which led us to providing exhaustive monitoring. During this time, we found asymptomatic cysts in two of the patients’, explains Dr Eulàlia Baselga, Head of the Dermatology Department at the SJD Barcelona Children's Hospital.

Genetic finding

A detailed analysis of biopsy specimens and endothelial cell samples from patients revealed that their normally functional PTEN gene is replaced by a non-functional copy in endothelial cells, in a process known as somatic uniparental disomy.

A recently published study in the scientific journal Cancer Discovery from the American Association for Cancer Research, ‘Somatic uniparental disomy of PTEN in endothelial cells causes vascular malformations in patients with PTEN Hamartoma Tumor Syndrome’—the preclinical phase for which was conducted on young mice—showed that PI3K pathway inhibitors like Rapamycin and Capivasertib could be effective in reducing overgrowth of associated blood vessels. In addition, Capivasertib and Alpelisib, the inhibitors recently approved for treating certain types of breast cancer, act directly upon the molecular processes that trigger the disease.

‘Our study has allowed us to identify a key genetic mechanism of the vascular malfunctions associated with PTEN hamartoma tumor syndrome. This discovery not only helps us better understand the disease, but also helps forge new diagnostic pathways and develop treatments that are more precise and effective for patients’, highlights Dr Sandra Castillo, Principal Investigator of the Pathobiology of Tumours and Vascular Malformations line of research at the SJD Research Institute.

Thinking to the future

Despite promising results, the scientific team emphasises that continued research is essential to discover the long-term therapeutic effects of these inhibitors. It is still not known for certain whether these treatments will alter the progression of the disease beyond reducing vascular malformations. Moreover, it is possible that the treatment will need to be chronic, as other types of vascular malformation have been shown to relapse after stopping medication.

The next steps in the research journey will focus on possible treatment resistance and will explore alternative therapeutic strategies, such as intermittent drug use or combining several inhibitors.

This study is a huge step forward in the understanding and treatment of a rare disease that has significant clinical implications, opening the door to future research that could improve the quality of life of patients with PHTS.