PI3K

Genetic aberrations in signaling pathways are the best current indicators of success for therapy, and there are more genetic aberrations in the PI3K pathway than any other pathway. Moreover, resistance to many other drugs such as Herceptin, Glevec, chemotherapies, and radiation can be shown to be due to activation of the PI3K pathway. The PI3K/PTEN pathway is a critical non-redundant intercept point in cell signaling that controls angiogenesis, apoptosis, migration, invasion, growth, and metastasis. Mechanistically, PI3K promotes cell proliferation and angiogenesis and inhibits apoptosis, while PTEN does just the opposite, controlling PI3K’s activity. Working together, PI3K/PTEN balance cellular function – recently coined the “Yin and Yang of cell survival.”

There are multiple targets along this pathway, both upstream and downstream of PI3K (such as VEGF, EGF, IGF, etc. upstream, and Akt, mTOR, Raf, Bcl-Abl, etc. downstream). Upstream targets, mainly growth factors and integrins, have multiple points of redundancy, and while some therapeutic benefit has been shown, the overall positive effects for the patient are limited. Downstream targets are showing potential therapeutic benefit in combination with traditional therapies. However, efficacy has been low and prone to drug resistance. Thus, we believe that because of PI3K’s critical nodal position in controlling these key up- and down-stream signals, PI3K inhibitors provide an exciting new therapeutic approach with tremendous biological rationale either alone or with other tyrosine kinase inhibitors, chemotherapies or radiation.

Semafore’s lead PI3 kinase inhibitor, SF1126, is currently in Phase I clinical trials in cancer patients. Additional PI3K inhibitors are being developed.