Larry Yin

Introduction: Prostate cancer is the most common cause of cancer related deaths in men worldwide¹. First-line treatment consists of androgen deprivation therapy, as androgens are necessary for prostate cancer survival and proliferation. Castration resistant prostate cancer (CRPC) no longer responds to androgen deprivation, often through direct activation of the androgen receptor (AR) or AR protein overexpression². 70-100% of CRPC progression sees an upregulation of the intracellular PI3K-AKT-mTOR signaling pathway, which regulates cell survival and proliferation³. Upregulation can be caused by several genetic defects, such as PTEN loss or AKT gain of function. The PI3K-AKT-mTOR pathway causes progression to CRPC through interactions between AR and PI3K-AKT-mTOR pathway and direct stimulatory feedback from the PI3K-AKT-mTOR pathway, though the exact mechanisms are unclear. Although there are promising therapies under investigation, the PI3K-AKT-mTOR pathway’s interactions with other signaling cascades, the presence of feedback/feedforward loops, and redundancy mechanisms are barriers to effective treatment³. Methods: Oral doses of buparlisib, a PI3K inhibitor, were given daily to subjects, with or without concurrent enzalutamide⁴. Cancer cultures were treated with AZD7328 and KU-0063974, AKT and mTOR inhibitors respectively, and assessed for autophagy markers and ERK activation. A patient-derived xenograft of prostate cancer was also treated⁵.Cell cultures and mouse xenograft models of CRPC were treated with PARP inhibitor olaparib and MET inhibitor crizotinib⁶. Nanomedicine platforms were created for gedatolisib (NanoGe) and cabazitaxel (NanoCa), both P13K inhibitors, and combination therapy (NanoCaGe). Effects of these treatments on cultures and mouse xenograft were compared to each other and the free drug format⁷.Results: Buparlisib had no effect on CRPC progression, with or without concurrent enzalutamide⁴.AZD7328 and KU-0063974 induced autophagy and inhibited frequency of tumor growth. In PTEN-loss mutants, compensatory activation of the Ras/MEK/ERK pathway was seen, which transduces extracellular signals to specific growth and repair genes⁵.Inhibition of MET suppressed the PI3K pathway and increased sensitivity to PARP inhibitors, indicated by lower levels of phosphorylate PI3K and AKT proteins when compared with monotherapy⁶.Nanomedicine platform increased the efficacies of both gedatolisib and cabazitaxel, with NanoCaGe seeing the greatest improvements in cure rates⁷.Conclusion: While the PI3K pathway strongly correlated with CRPC, inhibition of this pathway alone is insufficient due to activation of other signaling pathways that serve as  compensatory mechanisms. The most effective therapies are combination therapies that target PI3K as well as these other pathways.

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