Intellikine has developed a portfolio of novel drug candidates that selectively inhibit the PI3Kα isoforms as well as PI3Kα/β dual inhibitors, for the treatment of solid tumors.
The PI3K-Akt pathway is frequently upregulated in human tumors and PI3Ks are important regulators of cancer-related signaling pathways involved in cell proliferation, adhesion, survival and motility. One member, the PIK3CA gene encoding the p110α catalytic subunit, is frequently mutated in a broad spectrum of tumors including colon, breast, brain and lung. PIK3CA represents one of the most highly mutated oncogenes identified in human cancers. Analyses of PIK3CA mutations reveal that they increase the PI3K signal, stimulate downstream Akt signaling, and promote growth factor-independent growth and increase cell invasion and metastasis. In several tumors in which the PI3K pathway is activated by a combination of mutant PIK3CA and alterations in Ras, ERBB2/3, or PTEN, signaling to downstream elements such as Akt was mediated by the p110α isoform, and in part by the p110β isoform rather than by a combination of all class I PI3K isoforms. In fact, recent studies have delineated specialized functions in tumorigenesis for p110α and p110β. It is proposed that p110α carries the majority of the PI3K signal driven by PIK3CA mutations and/or oncogenic RTKs/Ras, whereas p110β responds to GPCRs as well as mediating PTEN-deficient tumorigenesis. In tumors with co-occurring mutations of multiple components of the PI3K pathway, selective inhibition of the p110α and/or p110β isoforms presents an attractive therapeutic strategy, especially for late-stage, aggressive and drug-resistant tumors.