PI3K signaling in cardiovascular and pulmonary diseases

The PI3K signaling pathway regulates diverse cellular functions, including survival, proliferation and metabolism, and deregulation of this axis has been implicated in a variety of pathological conditions, ranging from cancer to cardiovascular disease. Our research is focused on understanding the role of the PI3K signal transduction in two different disease contexts: 1) cardiac disease, with a main focus on the cardiomyopathy induced by anti-cancer agents (Cardio-Oncology arm), and 2) chronic respiratory disease, with a major emphasis on cystic fibrosis lung pathology (Airway disease arm) (Fig. 1). 

Cardiotoxicity is a major drawback of commonly employed anti-cancer agents, often requiring the use of lower and less effective doses and, in the worst-case scenario, treatment discontinuation. Among the most cardiotoxic therapies are anthracyclines, like doxorubicin (DOX), which remain a cornerstone in the treatment of several solid and hematological cancers. Although clinical evaluation can identify patients at risk of anthracycline-induced cardiotoxicity (AIC), there is currently no effective means for preventing this complication, primarily because of an incomplete understanding of the underlying molecular mechanisms. We believe that the early molecular alterations that occur in myocardial cells in response to DOX are still reversible and tractable, and their identification is key to the design of effective means for preventing the evolution of the disease towards an irreversible and intractable state. Our projects aim at pinpointing the early molecular signs of AIC by exploiting in vitro and in vivo murine and zebrafish models (Fig. 2), and by combining molecular and biochemical characterization with in vivo functional phenotyping and single cell RNA sequencing approaches. 

The second line of Ghigo’s lab research is dedicated to the study of the role of the PI3K signaling axis in the pathogenesis of airway diseases, with a special attention to the lung pathology of patients with cystic fibrosis (CF). CF, the most common among rare lethal genetic diseases, is caused by mutations in the gene encoding the Cystic Fibrosis Conductance Regulator (CFTR), a chloride channel activated by cyclic AMP, expressed on the apical surface of epithelial cells, and favoring mucus hydration. In CF patients, CFTR dysfunction results in abnormally dehydrated mucus, which clogs the airways and fuels recurrent infections and inflammation, eventually culminating in respiratory failure. The standard of care for CF patients includes the so-called CFTR modulators which, however, reinstate the function of the mutant channel only up to 60% of the wild-type protein. Furthermore, CF patients treated with CFTR modulators display a residual disease characterized by lung inflammation and infections. We showed that class I PI3Kγ is a key negative regulator of cAMP-mediated activation of the CFTR channel. We demonstrated that PI3Kγ functions as an A-kinase anchoring protein (AKAP) that tethers protein kinase A (PKA) in close proximity to its targets, cAMP phosphodiesterases (PDEs), favoring their phosphorylation and activation, and ultimately ensuring cAMP degradation. Accordingly, we designed a cell-permeable PI3Kγ mimetic peptide (PI3Kγ MP) that, by displacing the PI3Kγ-anchored pool of PKA, inhibits PDE4 and safely increases cAMP in the lungs upon inhalation. We showed that, in virtue of its ability to increase cAMP, the PI3Kγ MP can ensure three independent therapeutic effects in CF, namely airway smooth muscle relaxation, reduced pulmonary inflammation (Fig. 3) and maximization of the efficacy of CFTR modulators.