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

## TL;DR

Combining GHRH antagonist peptides with PI3K inhibitors increases cell death in prostate cancer, including therapy-resistant types.

## Contribution

A novel combination of GHRH antagonists and PI3K inhibitors is shown to enhance prostate cancer cell death.

## Key findings

- MIA-602/690 combined with PI3K inhibitors increased cell death in all prostate cancer types.
- The combination affects multiple pathways like apoptosis and proliferation.
- The acetate salt form of MIA-602/690 showed similar results in more clinically relevant conditions.

## Abstract

The increased use of potent androgen receptor antagonists has resulted in a rise in advanced prostate cancers resistant to androgen deprivation therapy with few treatment options. GHRH expression in cancers has led to the development of peptide antagonists (e.g., MIA-602 and -690) for therapeutic treatment. However, MIA-602/690 GHRH antagonists alone are not likely to be effective against advanced prostate cancer. We identified the novel combination of PI3K inhibitors + MIA-602/690 that increased cell death in all types of prostate cancer cells, including ones resistant to androgen deprivation therapy. The ability of MIA-602/690 and PI3K inhibitors to affect multiple signaling pathways may enhance cell death and optimize therapeutic benefit.

Background. 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. Methods/Results. We identified inhibitors of PI3Kα or PI3Kβ 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. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The 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. Conclusion. 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.