The results of in vitro and preclinical studies suggest that, due to adverse effects, current inhibitors of PI3K and Akt may have limited use in clinical practice. At present, the most promising inhibitors of PIK3/Akt/mTOR pathway for the treatment of prostate cancer are mTOR inhibitors, some of which are already in clinical use for other pathological conditions as well as for other malignancies.
Only two of the compounds that inhibit Akt activation, perifosine and celecoxib, have been investigated in the clinical setting. In a trial investigating the effects of perifosine in patients with metastatic CRPC (n=19), no complete or partial responses were detected and only four patients had a PSA stabilization for 12 weeks or more [122
]. There was, however, a decrease in the detection of circulating tumor cells in 11/14 of these patients after treatment. These results may be significant since circulating tumor cells are considered evidence of disseminated disease [123
], and decreases in circulating tumor cells have been shown to correlate with increased survival in patients with metastatic breast cancer [124
]. Long term follow up is needed to determine whether these effects of perifosine will result in clinical improvements. In a phase II study in men with biochemically recurrent, hormone-sensitive prostate cancer, perifosine administration resulted in PSA decreases in 5/24 patients; however, no patients met the predefined criteria for a true response (a 50% or greater reduction in PSA) [125
]. A phase II clinical trial investigating the use of celecoxib in patients with biochemically recurrent prostate cancer (n=40) after radiation or radical prostatectomy showed a significant inhibition of PSA doubling time [126
]. Three months after treatment initiation, 90% of patients had a lower PSA doubling time with 11/40 experiencing a decrease in absolute PSA levels. However, a trial of celecoxib vs.
placebo in a similar patient population (n=78) did not show any differences in PSA doubling time [127
]. Celecoxib in combination with docetaxel and estramustine in CRPC patients resulted in a median survival of 19.2 months, relatively similar to TAX 327 and SWOG 99-16 [128
]. Further trials, such as STAMPEDE, will help to determine the role of COX-2 inhibition in treating advanced prostate cancer and whether any anti-cancer activity is due to its Akt-inhibiting properties.
Clinical investigation of mTOR inhibitors in the oncologic setting is a relatively new, but promising area of investigation that started within the past decade. Rapamycin was initially developed as an immunosuppressive agent and was approved by the FDA in 1998 for this purpose [33
]. The pharmacokinetics of this drug is well known, with excellent absorption after oral dosing and peak concentrations at approximately 1.5 hours after administration. The incidence of severe toxicity reactions has been rare, and only mild adverse effects including hyperlipidemia, thrombocytopenia, leukopenia, diarrhea, skin rash, pneumonitis, and electrolyte abnormalities have been reported. There are also quickly accumulating data regarding pharmacologic profiles of rapamycin analogs showing that these analogs are well-tolerated and exhibit minimal negative side effects [129
Efficacy of mTOR inhibition was demonstrated in early phase clinical trials in a number of malignancies, and mTOR inhibitors are now in clinical development in endometrial cancer, breast cancer, glioblastoma, lymphoma, and sarcomas [135
]. CCI-779 was investigated in a large phase III trial in advanced renal cell carcinoma, and median overall survival was significantly increased vs. IFN-α (10.9 months vs. 7.3 months, p=0.008) [136
]. CCI-779 (temsirolimus) was subsequently approved by the FDA in 2007 for the treatment of advanced renal cell carcinoma.
In prostate cancer, there are several ongoing phase I and II clinical trials with mTOR inhibitors (). Some of these trials are designed in the neoadjuvant and/or the adjuvant setting. These trials are focused on analysis of key factors in mTOR signaling and their alterations in response to mTOR inhibition. Certainly, the ability to assess the molecular response to therapy is one of the central advantages of cell signaling modifiers. Molecular stratification of patients to mTOR inhibitor therapy may help to identify those patients most likely to benefit from treatment while sparing those patients who are unlikely to respond. Neoadjuvant use of mTOR inhibition could also provide an opportunity to target tumor cells before they have accumulated the large number of mutations that typically arise with advanced disease. PTEN
mutations and deletions within primary tumors have been associated with an increased risk of metastasis [33
] and early targeting may prove to be beneficial in preventing metastatic spread. Additionally, it has been suggested that mTOR inhibitors could be used as chemopreventive agents in patients who have deleted or inactivated PTEN
in benign prostate epithilium or PIN at the time of prostate needle biopsy [7
]. Because the clinical trials testing mTOR inhibitors are ongoing or still accruing patients, there are only limited results available at this time. A preliminary analysis of a phase II clinical trial of neoadjuvant administration of RAD-001 in patients prior to radical prostatectomy has not only showed that the drug is well tolerated but also that it decreases the levels of activated mTOR substrates in the primary tumor.1
A majority of the ongoing trials in prostate cancer are assessing mTOR inhibition in the setting of CRPC. One study in patients with metastatic CRPC is evaluating the cellular and molecular responses to RAD-001 by comparing pre- and post-treatment bone-derived tumor biopsies.2
Results of this trial, similar to the neoadjuvant studies assessing phenotypic changes in the primary tumor, will provide important information regarding the efficacy of these therapies on a molecular level.
Because of the heterogeneity of prostate cancer [137
] and the ability of tumor cells to undergo cellular alterations that allow survival under changing conditions, most of the trials investigating mTOR inhibition in CRPC utilize combinations of drugs. The majority of these trials are designed to provide a horizontal blockade within the cancer cell. Horizontal blockade refers to the simultaneous inhibition of multiple different targets. For example, inhibiting a MAP kinase at the same time as mTOR may block one of the key pathways that overlaps with the PI3K/Akt/mTOR pathway. Another approach to horizontal blockade involves targeting different cell types, such as targeting endothelial cells with a VEGF inhibitor, pericytes with a PDGF inhibitor, and/or osteoblasts with an endothelin A inhibitor, while also targeting the tumor cell directly [139
]. The second approach to combination therapy is to administer agents according to a vertical blockade rationale. A vertical blockade is designed to target multiple key factors within one specific pathway. For example, simultaneous inhibition of PI3K, Akt, and mTOR may be required to fully suppress activity of this pathway. Since upstream molecules in the mTOR pathway may be upregulated with administration of mTOR inhibitors—proposed as mechanism for mTOR inhibitor resistance [84
]—vertical blockade may prevent the shunting of upstream molecules down alternative signaling pathways. However, initial analysis of AP23573 used in combination with the epidermal growth factor inhibitor gefitinib in patients with advanced prostate cancer showed that only 5/29 patients had no disease progression at 12 weeks.3