Abstract 1063: Precision medicine and cancer drug repurposing in the management of vascular anomalies

Vascular anomalies are a heterogeneous group of rare diseases caused by defects in the early stages of vascular development that result in abnormal growth and development of vessels. The treatment typically consists of surgical approaches; unfortunately, many anomalies cannot be cured. Therefore, the goal of the treatment is to control the lesion, and progression or recurrence after an intervention is no exception. In the last 15 years, tremendous progress in understanding the molecular basis of the disease has been made, with alterations in more than 40 genes proven to be causal in the disease pathogenesis. Interestingly, such alterations are also found in many human cancers, which recently raised the question of whether repurposing anti-cancer drugs could be utilized in this setting. Tissue biopsies from 38 patients with vascular anomalies have been analyzed using different approaches ranging from Sanger sequencing to NGS-based detection. In 31 patients, known causal alterations of either germline or somatic origin were found. For the remaining seven patients, sampling issues were considered a cause of the negative result. Given that most patients suffered from a venous type of malformation, most alterations were found in TEK and PIK3CA genes, which are commonly altered in this subgroup. Other findings included alterations of KRAS, GLMN, PTEN, or IDH2 genes. TEK gene mutations were predominantly located in exon 17, which encodes for a part of the tyrosine kinase domain of the protein, with frequent L914F substitution being found in 12 cases. Identified PIK3CA gene mutations were all well-characterized activating alterations described in cancer-related context. Based on an identification of either TEK or PIK3CA mutation, 13 patients were administered targeted treatment using selective PI3K alpha subunit inhibitor alpelisib. For all patients, improvement in quality of life, lesion reduction and normalization of coagulation parameters was achieved. A deeper understanding of the pathophysiology of vascular anomalies can significantly contribute to patient stratification, identification of potential therapeutic targets, and overall better clinical management. At the same time, identifying potential therapeutic targets could lead to the administration of novel anti-cancer drugs within the concept of drug repurposing and better overall disease control compared to routinely used approaches. Supported by the Ministry of Health of the Czech Republic, grant nr. NU20-03-00240 and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU. Citation Format: Petra Pokorna, Renata Faberova, Olga Koskova, Martin Sterba, Hana Palova, Katerina Kozelkova, Robin Jugas, Dagmar Al Tukmachi, Tana Machackova, Jiri Sana, Peter Mudry, Jaroslav Sterba, Ondrej Slaby. Precision medicine and cancer drug repurposing in the management of vascular anomalies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1063.