Targeting PI3K isoform shows therapeutic promise in pancreatic neuroendocrine tumors

Researchers from the Institute of Biomedical Investigation of Bellvitge (IDIBELL; Barcelona, Spain) have identified the p110α isoform of PI3K as a potential therapeutic target in pancreatic neuroendocrine tumors (PanNETs). In a mouse model of PanNETs, selective inactivation of p110α PI3K was sufficient to block tumor progression and metastasis in a mice model.

It is known that mutations in the PI3K signaling pathway occur in 16% of patients with PanNETs. This recent investigation – published in Clinical Cancer Research – contributes to our understanding of PI3K in PanNETs and potentially broadens the therapeutic field in highlighting the potential of targeting the PI3K pathway.

Design of targeted therapies for this disease has been complicated by the inherent heterogeneity of the malignancy.  Resistance to the currently used mTOR targeted therapy is becoming more frequent, highlighting a need for new effective treatments.

The research team led by Mariona Graupera (IDIBELL), firstly investigated the activation of the PI3K pathway in samples of human panNETs and RIP1-Tag2 mice (panNET model). These RIP1-Tag2 mice were then treated with generic (GDC-0941) and p110α-selective (GDC-0326) inhibitors of PI3K.

Results from these studies demonstrated that both human samples and mouse models of panNETs display upregulated PI3K pathway activity compared with healthy tissue.  It was also found that genetic or pharmacological inhibition of the PI3K isoform p110α reduced growth of the tumor and surrounding vasculature.

This selective intervention of the PI3K pathway in panNETs not only suggests a potential therapeutic for these pancreatic tumors, but also sheds further light on the role of kinases in cancers as a whole – implicating it in metastatic spread.  Results from this study may aid in the therapeutic development of isoform-specific PI3K inhibitors to treat cancers of all types.

Sources: Soler A, Figueiredo AM, Castel P et al. Therapeutic benefit of selective inhibition of p110-alpha PI3-kinase in pancreatic neuroendocrine tumors. Clin Cancer Res. DOI: 10.1158/1078-0432.CCR-15-3051 (2016); IDIBELL press release