by ecancer reporter Janet Fricker

Inactivation of the p110 delta isoform of phosphoinositide-3-OH kinase (PI(3)K) in mice protects against a broad range of cancers, including non-haematological solid tumours, reports a study in a letter to Nature.

The UK and Italian researchers furthermore found that inhibition of the p110 delta isoform in a mouse model of pancreatic cancer led to reductions in occurrence of metastases and prolonged survival.

The p110 delta inhibitor, idelalisib, is already showing remarkable therapeutic efficacy in chronic lymphocytic leukaemia (CLL) and non-Hodgkin’s lymphoma.

But since p110delta is primarily expressed in leukocytes, drugs against p110 delta  have not been considered for the treatment of solid tumours.

In the current study Bart Vanhaesebroeck, from University College, London, and Emilio Hirsch, from the University of Turin, Italy, identified PI(3) K as a druggable target since it was critically required for the immunosuppressive function of regulatory T cells( Treg ).

To test whether host p110 delta activity affects tumour growth, the investigators inoculated weakly immunogenic synergistic cancer cell lines into in mice in which endogenous p110d kinase was in active ( dD910A mice).

In comparison to wild-type mice they showed that the dD910A mice were more resistant to B16 melanoma, had reduced tumour incidence and lymph node metastasis.

Furthermore, administration of PI-3065, a small molecule inhibitor with selectivity for p110 delta, was shown to suppress tumour growth and metastasis to a similar extent as genetic inactivation of p110 delta.

In an animal model of model of pancreatic ductal adenocarcinoma administration of PI-3065 prolonged survival and reduced the incidence of macroscopic metastases and other disease related pathologies.

“Our work suggests that p110 delta inhibitors, by disrupting the function of T reg and possibly of MDSCs (myeloid derived suppressor cells), have the potential to shift the balance from immune tolerance towards effective anti-tumour immunity.

This provides a rationale for p110 delta inhibition both in solid and haematological cancers, possibly as an adjuvant to cancer vaccines, adoptive cell therapy, or other strategies that promote tumour-specific immune response,” conclude the authors.

Reference

K Ali, D Soond, R Pineiro, et al. Inactivation of PI(3)K p110d breaks regulatory T-cell mediated immune tolerance to cancer. Nature