Periodic Reporting for period 2 - PROSPECTS (PIK3CA-Related Overgrowth Syndrome, Pluripotency, Expression in speCific Tissue and Secretion)
Période du rapport: 2022-09-01 au 2024-02-29
Overgrowth syndromes are rare genetic disorders defined by tissue hypertrophy that can be either localized or generalized. In most cases, the mutations are not inherited but occur during embryogenesis, leading to somatic mosaicism. The genes involved in overgrowth syndromes are not well characterized but most appear to be part of the PIK3CA/AKT/mTOR pathway, a major actor in cell growth and proliferation. Among the different genes, gain-of-function mutations of PIK3CA seem to have a prominent role. The clinical presentation of patients with PIK3CA gain-of-function mutations is extremely broad owing to mosaicism but also the tissue involved. Patients usually have complex tissue malformations, including abnormal vessels, anarchic adipose tissue, muscle hypertrophy and/or bone deformation. Since 2014, patients with overgrowth syndrome harboring a PIK3CA mutation have been included in the PIK3CA-related overgrowth spectrum (or syndrome) (PROS) group.
With the support of the European Research Council (ERC Starting Grant n°679254 and Proof of Concept n°737546), we generated a mouse model of PROS that, for the 1st time, recapitulates the patient phenotype, identified BYL719, a PIK3CA inhibitor undergoing development in oncology, as a potential therapeutic for PROS and demonstrated the efficacy of this drug in our mouse model. We then showed the efficacy of the drug in patients with severe form of PROS.
However, if it is true that the drug is improving all patients, the response rate to treatment is variable ranging from good to exceptional response as assessed by clinical and imaging parameters. Interestingly, we did not find any correlation between the efficacy of BYL719 and the type of PIK3CA mutation. Nevertheless, we observed that the tissues that were affected conditioned the response to treatment. Indeed, vascular and adipose tissue malformations were extremely sensitive to PIK3CA inhibition with reductions in color, size and volume while bone malformations were resistant. Furthermore, while it is accepted that the disease is only due to mosaicism, we now have clues demonstrating that the physiopathology is much more complex.
In this proposal, we aimed to decipher the physiopathology of PROS by developing new preclinical mouse models. We will also open new perspectives for patients by identifying biomarkers and potential new therapeutic targets in case of occurrence of BYL719 resistance. Lastly, following incidental observation from preliminary data that we have generated, we will investigate the role played by PIK3CA activation in cell fate determination. These findings will be extrapolated to cancer and developmental biology, 2 fields where PIK3CA plays a critical role.
With the support of the European Research Council (ERC Starting Grant n°679254 and Proof of Concept n°737546), we generated a mouse model of PROS that, for the 1st time, recapitulates the patient phenotype, identified BYL719, a PIK3CA inhibitor undergoing development in oncology, as a potential therapeutic for PROS and demonstrated the efficacy of this drug in our mouse model. We then showed the efficacy of the drug in patients with severe form of PROS.
However, if it is true that the drug is improving all patients, the response rate to treatment is variable ranging from good to exceptional response as assessed by clinical and imaging parameters. Interestingly, we did not find any correlation between the efficacy of BYL719 and the type of PIK3CA mutation. Nevertheless, we observed that the tissues that were affected conditioned the response to treatment. Indeed, vascular and adipose tissue malformations were extremely sensitive to PIK3CA inhibition with reductions in color, size and volume while bone malformations were resistant. Furthermore, while it is accepted that the disease is only due to mosaicism, we now have clues demonstrating that the physiopathology is much more complex.
In this proposal, we aimed to decipher the physiopathology of PROS by developing new preclinical mouse models. We will also open new perspectives for patients by identifying biomarkers and potential new therapeutic targets in case of occurrence of BYL719 resistance. Lastly, following incidental observation from preliminary data that we have generated, we will investigate the role played by PIK3CA activation in cell fate determination. These findings will be extrapolated to cancer and developmental biology, 2 fields where PIK3CA plays a critical role.
To achieve these objectives, we developed multiple genetically modified preclinical experimental models and utilized highly innovative technologies such as cell-scale information analysis.
The funding for this project has improved our understanding of the mechanisms involved in these syndromes, better characterizing them and adapting treatments in a personalized manner. This has translated into the publication of the publication of 5 articles ( and 6 additional are currently under review) in high-ranking international scientific journals, the discovery of innovative new treatments for these rare diseases, more than 50 international invitations to present these results, notably in major universities, the filing of 9 patents, out of which 6 are under licensing contracts with pharmaceutical industries, and numerous national and international awards. In addition, we pushed the development of alpelisib (BYL719) the drug that we identified toward US FDA approval for patients with PROS aged of at least 2 years (April 2022).
The funding for this project has improved our understanding of the mechanisms involved in these syndromes, better characterizing them and adapting treatments in a personalized manner. This has translated into the publication of the publication of 5 articles ( and 6 additional are currently under review) in high-ranking international scientific journals, the discovery of innovative new treatments for these rare diseases, more than 50 international invitations to present these results, notably in major universities, the filing of 9 patents, out of which 6 are under licensing contracts with pharmaceutical industries, and numerous national and international awards. In addition, we pushed the development of alpelisib (BYL719) the drug that we identified toward US FDA approval for patients with PROS aged of at least 2 years (April 2022).
During the period, we identified new and unexpected physiopathological mechanisms. Indeed, we found that PIK3CA mutated cells have the ability to secrete molecules that recruit adjacent cells and activate the PIK3CA pathway through a non cell autonomous way. We are exploring these molecules that could represent new therapeutic targets.
Furthermore, we determined that mutations resulting in increased PI3KCA function trigger molecular processes capable of altering the cellular differentiation towards a different cell type. This effect varies in intensity based on the mutation dosage.
Lastly, we unearthed two previously unknown drugs that have exhibited highly promising results in mouse models and then in patients with disorders related to PIK3R1 and vascular malformations linked to KRAS.
Furthermore, we determined that mutations resulting in increased PI3KCA function trigger molecular processes capable of altering the cellular differentiation towards a different cell type. This effect varies in intensity based on the mutation dosage.
Lastly, we unearthed two previously unknown drugs that have exhibited highly promising results in mouse models and then in patients with disorders related to PIK3R1 and vascular malformations linked to KRAS.