Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer

Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 300 Brookline Avenue, Boston, MA 02215, USA.
Cancer biology & therapy (Impact Factor: 3.63). 03/2007; 6(2):195-201. DOI: 10.4161/cbt.6.2.3588
Source: PubMed

ABSTRACT Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway is a potentially useful therapeutic strategy in the treatment of advanced prostate cancer. However mTOR antagonists used as single agents are not likely to result in dramatic clinical responses, so that it is useful to identify prospective agents that might be useful in combination. We treated CWR22Rv1 and LNCaP prostate cancer cells with an mTOR inhibitor, rapamycin, alone, or in combination with either of two receptor protein kinase (RTK) inhibitors. We assessed the effects of these treatments on cell survival and activation of down-stream mTOR target proteins. Treatment with either PD16839, an EGFr antagonist, or imatinib mesylate (Gleevec), a PDGFr, c-kit and bcr/abl antagonist, enhanced the anti-proliferative effects of rapamycin. We therefore assessed the effects of treatment with the RTK antagonist alone and in combination with rapamycin on mTOR targeted proteins. RTK antagonists alone had no effect or paradoxically increased phosphorylation of the mTOR targeted proteins, p70 S6 kinase and ribosomal S6. In contrast, when these cells were treated with either RTK antagonist in the presence of rapamycin, there was a dramatic decrease in phosphorylation of these two mTOR-targeted proteins. These effects were not mediated through phospho-AKT. Since two separate RTK antagonists had additive antiproliferative effects in combination with an mTOR antagonist and were associated with a dramatic decrease in mTOR targeted proteins in cells with or without PTEN expression, the strategy deserves further evaluation for the treatment of prostate cancer.

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    • "It is considered that single-agent inhibition may induce tumor cells to activate alternative pathways (Chaturvedi et al., 2009; Zuo et al., 2010). Multiple strategies to inhibit PI3K/ AKT pathway have been proposed and are in ongoing clinical trials (Buck et al., 2006; Faivre et al., 2006; Masiello et al., 2007; Wang et al., 2007). Antagonism of cell surface receptor and nonreceptor kinases could potentially disrupt the PI3K pathway by eliminating the stimulus for PI3K activation. "
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    ABSTRACT: This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor (EGFR) or/and mammalian target of rapamycin( mTOR) inhibitors with two endometrial cancer lines HEC-1A and Ishikawa. Treatment was with the EGFR inhibitor RG14620, the mTOR inhibitor rapamycin, and the conventional cytotoxic drug paclitaxel, alone or in combination. The 50% inhibitory concentration (IC50) and cell viability were determined by the MTT assay. Multiple drug effect/ combination indexes (CI) analysis was applied to assess interactions between paclitaxel and the two inhibitors. Apoptosis and cell cycling were evaluated by flow cytometry analysis. Western blotting was performed to evaluate the related protein alteration in PI3K/AKT signaling pathway. RG14620, rapamycin and paclitaxel showed obvious dose-dependent growth inhibition with time. The IC50 of paclitaxel at 24 hours decreased significantly when pretreated with low doses of RG14620 and Rapamycin alone or in combination. Moreover, combination index (CI) of paclitaxel with each inhibitor was larger than 1, indicating a synergistic effect between pairs of drugs in these two cell lines. FACS analysis showed the cell apoptosis rate increased with a synergistic effect. On Western blotting, activation of PI3K/AKT pathway was detected in both two cell lines in the control case. When paclitaxel was used as a single-agent or in combinations, the protein expression of PI3K/AKT pathway totally abated, especially in HEC-1A cells, suggesting a role in chemoresistance. The combination of three drugs induced the greatest over-expression of caspase-3. Combining targeted inhibitors with cytotoxic chemotherapy appears to be a promising strategy for the effective treatment of endometrial cancer which merits further clinical investigation.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(11):2951-7. · 2.51 Impact Factor
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    • "Whereas rapamycin is a well known cell growth inhibitor and has earlier been reported to reduce LNCaP cell growth, androgens are known to increase LNCaP proliferation [37] [38] [39]. It was therefore of interest to assess the effect of rapamycin in combination with androgen on growth characteristics of LNCaP cells. "
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    ABSTRACT: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR-PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo. Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth. Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression. These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.
    Cellular oncology: the official journal of the International Society for Cellular Oncology 01/2010; 32(1-2):11-27. DOI:10.3233/CLO-2009-0487 · 4.17 Impact Factor
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    • "Synergistic effects of rapamycin and EGFR TKIs have been observed in several in vitro systems, including glioblastoma multiforme (Hjelmeland et al., 2007; Rao et al., 2005; Wang et al., 2006), prostate cancer (Buck et al., 2006; Masiello et al., 2007), pancreatic cancer (Buck et al., 2006), squamous cell carcinoma (Jimeno et al., 2007), renal cell carcinoma (Costa et al., 2007; Gemmill et al., 2005), leukemia (Mohi et al., 2004), cervical carcinoma (Birle and Hedley, 2006), and non-small cell lung cancer (Buck et al., 2006). Several of these studies extended the efficacy of these combinations to xenograft experiments (Birle and Hedley, 2006; Buck et al., 2006; Jimeno et al., 2007). "
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    ABSTRACT: The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.
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