Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhances Cell Death in Prostate Cancer

Antagonists of GHRH have experimental therapeutic value but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that in combination with MIA-602 or -690 GHRH antagonists increase cell death in all types of prostate cancer. We identified inhibitors of PI3Ka or PI3Kb that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. Results revealed that MIA-602/690 alone decreased androgen receptor and likely enhanced PI3K (negative feedback), which is then countered by addition of PI3K inhibitors. Furthermore, MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switch to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Ka/b, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. Identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40-50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis. The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy.