On the basis of our previous work defining the molecular rationale for combined targeting of the PI3K and AR pathways in <i>PTEN</i> loss prostate cancer, the first clinical trial was recently reported demonstrating a significant benefit for combination therapy in patients with metastatic prostate cancer.
<b/> PI3K pathway alterations are frequently recurrent in metastatic prostate cancer and are associated with the development of currently incurable castration-resistant disease.
Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo.
Genetic inactivation of PTEN through either gene deletion or point mutation is reasonably common in metastatic prostate cancer and the resulting activation of phosphoinostide 3-kinase, AKT and mTOR provides a major therapeutic opportunity in this disease as mTOR inhibitors, HSP90 inhibitors and PI3K inhibitors begin to enter clinical development.