PI3K signalling constitutes a key molecular node controlling growth, migration, survival, and metabolism. The PI3K family of enzymes has eight catalytic isoforms that are grouped into three main classes, with the class I PI3Ks directly activating signal transduction pathways. The production of PtdIns(3,4,5)P3 (PIP3), the main product of class I PI3Ks is predominantly counteracted by the lipid phosphatase PTEN, a pivotal tumour suppressor gene. Genetic alterations that result in activation of class I PI3K are common events in cancer, including somatic mutational activation of PIK3CA and inactivation of PTEN. Recently, equivalent monogenic alterations have been found in rare diseases. PIPgen was born from the idea that witnessing translational and clinical studies in the PI3K and cancer field can be extremely informative for the assessment and treatment of PI3K monogenic rare diseases, and vice versa.
In Europe, there are approximately 15000 people affected with a PI3K-related rare disease. PI3K-related monogenic rare diseases can be grouped as: (1) overgrowth syndromes (PTEN, PIK3CA), (2) primary immunodeficiencies (PIK3CD, PTEN) and (3) cognitive deficiencies (PTEN, PIK3CD). Oncogenic mutations in PIK3CA mainly occur somatically, in line with experimental evidence that demonstrates that the expression of PIK3CA hotspot mutations in the germline results in embryonic lethality. On the contrary, germline activating mutations in PIK3CD and heterozygous loss of function mutations in PTEN are compatible with life but lead to a primary immune disorder and the PTEN hamartoma tumour syndrome (PHTS). Given the strong link between PI3K deregulation and cancer, multiple small molecules targeting the PI3K pathway have been generated. Despite initial challenges, a more productive phase in PI3K drug development (mainly focused on targeting individual isoforms of PI3K) has now matured with four PI3K inhibitors approved for clinical use in cancer and several high-quality drugs making their way to the clinic.
With all this in mind, PIPgens aims to better understand the PI3K/PTEN pathway in both pathological scenarios to not only focus on the basic science but also to make a real therapeutical impact