A New Strategy to Increase Proteotoxic Cell Death in Cancer. My laboratory is interested in discovering new experimental therapeutic strategies in prostate cancer (PCa) and hepatocellular carcinoma (HCC). Our results showed that the combination of the pan-cyclophilin (Cyp) inhibitor Rencofilstat (RCF) and the proteasome inhibitor ixazomib (Ixz) amplified proteotoxic stress and cell death in multiple PCa (including aggressive castration-resistant PCa [CRPC] and neuroendocrine PCa [NEPC]) and HCC cells. Our results also showed RCF + Ixz was not toxic in non-cancer cells. Cyclophilins are required for proper folding of proteins so inhibitors of cyclophilins will increase unfolded proteins, which will further accumulate when combined with proteasome inhibitors to amplify proteotoxic stress, and lead to cancer cell death. RCF + Ixz preferentially activated the XBP1s protection mechanism of unfolded protein response against proteotoxic stress. Although elevated XBP1s has an initial pro-survival role, unresolved responses to excessive proteotoxic stress and sustained XBP1s resulting from RCF + Ixz triggers cell death. Results support the hypothesis that XBP1s initially acts as a pro-survival factor but if it is maintained for longer periods of time (as with RCF + Ixz), XBP1s switches to a pro-cell death function. Drug targets for RCF (cyclophilins A, B) are important in mediating the effect. Initial data in a mouse model of HCC suggests the RCF + Ixz combination may have efficacy.

Searching for FDA Approved Drug Combinations with Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides to Increase Prostate Cancer Cell Death. The Andrew Schally laboratory has developed several peptide antagonists against GHRH for use against multiple cancers. The rationale is that since receptors for GHRH are often highly expressed in cancers, addition of GHRH antagonists will block key signals important for cancer cell proliferation. Key results in mouse models of PCa have confirmed the efficacy of GHRH antagonists. However, it is likely that treatment of PCa and the more aggressive forms CRPC and NEPC with GHRH antagonists as single agents will not be sufficient for optimal efficacy. My laboratory searched a series of FDA approved anti-cancer drugs that in combination with GHRH antagonists can increase PCa/CRPC/NEPC cell death. PI3Kalpha (Alpelisib) and PI3Kbeta (AZD8186) inhibitors were the most effective FDA approved drugs in combination with the GHRH antagonists MIA-602 and MIA-690. We propose that when GHRH receptor is blocked by GHRH antagonists, PI3Kalpha or beta have adaptive pro-survival responses. Therefore, combination of PI3Kalpha (Alpelisib) or PI3Kbeta (AZD8186) + GHRH antagonists may improve efficacy in PCa/CRPC/NEPC therapy. This is significant because loss of PTEN tumor suppressor occurs in 40-50% PCa, leading to PI3K hyperactivation.