PI3K

The PI3 kinases (PI3K) belong to a family of signal-transducing enzymes that mediate key cellular functions in cancer and immunity. The PI3K-gamma isoform plays an important role in immune cell function and migration, as well as supporting the function of myeloid cells in the tumor microenvironment.1 Because of this, targeting PI3K-gamma in immune cells could alter the balance from an immune-suppressive to a pro-inflammatory environment, leading to tumor growth inhibition.2,3

Infinity is advancing IPI-549, an oral immuno-oncology development candidate that selectively inhibits PI3K-gamma. Preclinical data in multiple solid tumor models have demonstrated that IPI-549 targets immune cells and alters the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition.4 Additionally, in preclinical models, IPI-549 has demonstrated the ability to enhance the activity of and to reverse tumor resistance to checkpoint inhibitors5,6, a class of medicines that has shown promise for the treatment of several types of cancer.

As the only selective PI3K-gamma inhibitor in clinical development, IPI-549 has the potential to offer a unique approach within the emerging field of immuno-therapy. A Phase 1 study of IPI-549 in patients with advanced solid tumors is ongoing.7

 

 

[1] Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kƴ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011;19(6):715-727.

[2] Joshi S, Singh AR, Zulcic M, et al. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res 2014 12 (10);1520-1531.

[3] Gunderson, AJ, Kaneda MM, Tsujikawa T, et al. Bruton tyrosine kinase–dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 2016 6(3);270-285.

[4] Henau, O., Merghoub, T., Winkler, D. et al. Checkpoint blockade therapy is improved by altering the immune suppressive microenvironment with IPI-549, a potent and selective inhibitor of PI3K-gamma, in preclinical models. American Association for Cancer Research Annual Meeting 2016, Abstract #554.

[5] Kaneda, M.M., Messer, K.S., Ralainirina N. et al. Nature, Advanced Online Publication, September 2016, http://www.nature.com/nature.

[6] Rausch, M., Tchaicha, Tibbitts, T. et al. The PI3K-gamma inhibitor, IPI-549, increases antitumor immunity by targeting tumor-associated myeloid cells and remodeling the immune-suppressive tumor microenvironment. Presented at Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (Poster B032), 2016.

[7] www.clinicaltrials.gov, NCT02637531.

.