Our discovery of PI3Kdelta: from the gene to the clinic

A substantial focus of our work to date has been on the PI3Kdelta isoform of PI3K, identifying this PI3K family member as a new drug target in auto-immunity, inflammation 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, amongst other the creation of 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, most recently, as a target to stimulate the body’s immune response to both solid and haematological cancers [8]. We are now involved in clinical trials to test this concept, in collaboration with Amgen, Cancer Research UK and Christian Ottensmeier and his team at the Southampton Cancer Research UK Centre. Gilead is also testing PI3Kdelta inhibitors in pancreatic cancer and triple negative breast cancer.

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. Other companies that developed PI3Kdelta inhibitors, many of whom we collaborate with, include ICOS/Calistoga (now Gilead), Amgen, Intellikine, TG Therapeutics, Incyte, Xelexis, Karus Therapeutics and GlaxoSmithKline.

Targeting PI3Kdelta has been the most successful clinical PI3K inhibitor development effort to date, for the following indications: 

1. Three PI3K inhibitors have now been approved for specific B-cell lymphomas, all sharing the ability to inhibit PI3Kδ. In 2014, the PI3Kdelta inhibitor Idelalisib/Zydelig from Gilead was approved for the treatment of specific blood cancers. Indeed, PI3Kdelta inhibitors have shown high efficacy in specific B-cell malignancies, such as in chronic lymphocytic leukaemia (see amongst others Ref. [9]). 
2. PI3Kdelta inhibitors are also being tested in airway inflammation. 
3. 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. 
4. PI3Kdelta inhibitors could also provide help 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.

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.
9. Vanhaesebroeck, B. and Khwaja, A., PI3Kdelta inhibition hits a sensitive spot in B cell malignancies. Cancer Cell, 2014. 25(3): p. 269-71.