BKM120 Zytiga Combo

BKM120 is a potent inhibitor of PI3K which augments total androgen blockade with Zytiga. PI3K mediates the cell survival pathway by inhibiting apoptosis (cell death). Insulin signals this survival pathway through the IGFR receptor which signals through the IGFR-PI3K-PIP2-Akt pathway to generate active phospho pAkt which phosphorylates the FOXO transcription factor to inactivate it. FOXO transcribes the apoptotic proteins so inhibiting FOXO by active Akt prevents cells undergoing apoptosis and keeps these cells alive. So the prostate cancer cells are surviving on insulin by signalling through the IGFR/PI3K/Akt pathway. No wonder inhibitors of this pathway are important since they will induce apoptosis of cancer cells causing tumours to regress. In practice PI3K inhibitors do not work very well when used alone but do work well when combined with other treatments. Clinical trials show that BKM120 increases the response rate when comibined with Paclitaxel. In fact there are several ongoing clinical trials with BKM120 against various forms of cancer including prostate cancer, breast cancer and lung cancer.

There is emerging evidence that cancer cells surviving Zytiga therapy are doing so by using this insulin promoted singalling pathway of PI3K/Akt so using a PI3K inhibitor in combination with Zytiga makes perfect sense. The natural PI3K inhibitor salvestrol Q40 is present in Salvestrol Platinum which has been combined with Zytiga with promising results. The pharmaceutical industry are now catching up with mother natures PI3K inhibitors. The semi synthetic PI3K inhibitor PX-866 is a derivative of the natural compound Wortmanin which is also in clinical trials in combination with Zytiga. Many drug companies are now jumping on the bandwagon and several new drug candidates are in progress that inhibit members of the PI3K-Akt-mTOR pathway. Clinical trials are now underway to evaluate the combination of BKM120 with Zytiga.

BKM120 is from Novartis Pharmaceuticals who have succeeded in producing a really well designed drug that has activity against all 4 isoforms of PI3K inhibiting the catalytic subunits p110 alpha, beta, gamma, and delta with IC50's from 30 to 160 nM.

The molecular structure of BKM120 shows that it is a di morpholino substituted pyrimidine. It has a half life of 40 h with a maximum tolerated dose of 100 mg daily. No significant side effects were reported from trials on BKM120 and show this drug is well tolerated.