Targeted Therapy for Advanced Prostate Cancer: Inhibition of the PI3K/Akt/mTOR Pathway

Abstract

A large number of novel therapeutics is currently undergoing clinical evaluation for the treatment of prostate cancer, and small molecule signal transduction inhibitors are a promising class of agents. These inhibitors have recently become a standard therapy in renal cell carcinoma and offer significant promise in prostate cancer. Through an understanding of the key pathways involved in prostate cancer progression, a rational drug design can be aimed at the molecules critical to cellular signaling. This may enable administration of selective therapies based on the expression of molecular targets, more appropriately individualizing treatment for prostate cancer patients.One pathway with a prominent role in prostate cancer is the PI3K/Akt/mTOR pathway. Current estimates suggest that PI3K/Akt/mTOR signaling is upregulated in 30-50% of prostate cancers, often through loss of PTEN. Molecular changes in the PI3K/Akt/mTOR signaling pathway have been demonstrated to differentiate benign from malignant prostatic epithelium and are associated with increasing tumor stage, grade, and risk of biochemical recurrence. Multiple inhibitors of this pathway have been developed and are being assessed in the laboratory and in clinical trials, with much attention focusing on mTOR inhibition. Current clinical trials in prostate cancer are assessing efficacy of mTOR inhibitors in combination with multiple targeted or traditional chemotherapies, including bevacizumab, gefitinib, and docetaxel. Completion of these trials will provide substantial information regarding the importance of this pathway in prostate cancer and the clinical implications of its targeted inhibition. In this article we review the data surrounding PI3K/Akt/mTOR inhibition in prostate cancer and their clinical implications.

Molecular genetics of prostate cancer: new prospects for old challenges

“…Therefore, recent approaches have been aimed at targeting signaling pathways activated in advanced prostate cancer, including the Akt/mTOR and MAPK signaling pathways. The evaluation of Rapamycin and related compounds (Rapalogs) that target mTOR signaling in preclinical trials in genetically engineered mutant mice and in human clinical trials suggest that these may not be effective as single agents (Sawyers 2003;Garcia-Echeverria and Sellers 2008;Morgan et al 2009). However, combination therapy using Akt/mTOR inhibitors in conjunction with first-line chemotherapy or agents that target other key signaling pathways such as the Erk MAPK pathway may be highly effective, as has been suggested by preclinical studies in which combination therapy effectively blocks castrationresistant prostate cancer in mice (Kinkade et al 2008).…”

Prostate cancer: the need for biomarkers and new therapeutic targets

“…Also, AR activates MAPK and EGFR. Moreover, EGF is able to induce up-regulation of interleukin-6 (IL-6) (Morgan et al, 2009).…”

“…Polymorphisms also aid the determination of PCa progression (single nucleotide polymorphisms at C-509T correlate with lower risk of aggressive PCa) Tissue Predictive Soulitzis et al, 2006;Faria et al, 2007;Brand et al, 2008 Trans-membrane prote- Ohta et al, 2003;Kumano et al, 2009;Almasi et al, 2011 underway (Morgan et al, 2009). The verification that loss of PTEN expression results in a down-regulation of CXCR4-mediated events and in the subsequent activation of PI3K/AKT and ERK1/2, also drew attention to the promising antagonistic effect of this receptor (Chetram et al, 2011).…”

Epidermal Growth Factor Receptor (EGFR) Phosphorylation, Signaling and Trafficking in Prostate Cancer

“…The PI3K/Akt pathway plays an important role in human cancers including prostate carcinoma (Chin & Toker, 2009;de Souza et al, 2009;Morgan et al, 2009;Qiao et al, 2008). Akt was initially identified as an oncogene within the murine leukemia virus AKT8 (Staal, 1987;Staal & Hartley, 1998).…”

“…Receptor tyrosine kinases such as EGFR and IGF-1R can activate PI3K at the cell membrane, initiating the PI3K/Akt signaling cascade. Once activated, PI3K phosphorylates phosphatidylinositol-4,5-diphosphate (PIP2), leading to accumulation of phosphatidylinositol-3,4,5-triphosphate (PIP3) (Morgan et al, 2009). PIP3 recruits Akt and phosphoinositide dependent protein kinase 1 (PDK1) to the cell membrane, where Akt is phosphorylated at Thr-308 by PDK1 and at Ser-473 via an unknown mechanism (de Souza et al, 2009).…”