Our discovery of PI3Kdelta: from the gene to the clinic

A focus of our work has been on PI3Kdelta, identifying this PI3K family member as a new drug target in immunity dysregulation and cancer. 

In 1997, we cloned the PI3Kdelta gene and found that it is highly expressed in white blood cells [1]. We subsequently showed that p110delta has selective functions in cells compared to other PI3K family members [2, 3]. Our studies generated the first mouse models of PI3Kdelta inactivation [4, 5], revealed key functions for PI3Kdelta, such as in adaptive immunity [4], allergy [5] and leukaemia [6, 7] and as a target to stimulate the body’s immune response to both solid and haematological cancers [8].

We were involved in the development of the first PI3Kdelta inhibitors, in a drug development programme with Piramed Ltd, which was acquired by Roche in 2008. In 2014, a PI3Kdelta inhibitor (Zydelig from Gilead Sciences) was the first PI3K inhibitor to be approved, namely for the treatment of specific blood cancers. Three PI3K inhibitors have now been approved for specific B-cell lymphomas. 

PI3Kdelta inhibitors have also been approved for people who carry an activating PI3Kdelta gene mutation that predisposes them to the so-called Activated PI3Kdelta Syndrome (APDS). Children with APDS often die early because they cannot fight infections. Their lungs are most often also badly damaged because of infections and scarring.

There is great hope that PI3Kdelta inhibitors could also be used to stimulate the body’s own immune response to cancer, in so-called cancer immunotherapy. This originates from work led by Khaled Ali (now at GSK), Klaus Okkenhaug (Cambridge) and Genentech (San Francisco, US) that identified PI3Kdelta (Nature 2016:535:580).

Proof-of-concept include studies were performed in head and neck cancer (Nature 2022:605:741) in a collaboration between Cancer Research UK, Amgen (San Francisco), Pandurangan Vijayanand (La Jolla Institute for Immunology, La Jolla, CA) and led by Christian Ottensmeier (Liverpool, UK).

A well-tolerated PI3Kdelta inhibitor from iOnctura is now being taken forward in uveal melanoma and lung cancer by iOnctura. iOnctura recently announced an €80m Series B financing to progress PI3Kdelta and other pipeline assets through Phase 2 trials.

References

1. Vanhaesebroeck, B., et al., P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A, 1997. 94(9): p. 4330-5.
2. Vanhaesebroeck, B., et al., Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol, 1999. 1(1): p. 69-71.
3. Sawyer, C., et al., Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta. Cancer Res, 2003. 63(7): p. 1667-75.
4. Okkenhaug, K., et al., Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science, 2002. 297(5583): p. 1031-4.
5. Ali, K., et al., Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature, 2004. 431(7011): p. 1007-11.
6. Billottet, C., et al., A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene, 2006. 25(50): p. 6648-59.
7. Billottet, C., et al., Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation. Cancer Res, 2009. 69(3): p. 1027-36.
8. Ali, K., et al., Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature, 2014. 510(7505): p. 407-11.