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Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic target in endometrial cancer.

1. Introduction

Endometrial cancer (EC) is the sixth most common gynecological cancer, causing approximately 74,000 deaths worldwide in 2008 [1]. It is speculated that during 2013,49,560 new cases and 8, 190 deaths will occur in the USA [2]. The majority of EC cases are sporadic but there is a familial predisposition in up to 10% of the cases [3]. According to Bokhman [4], there are two types of endometrial carcinomas: type 1 endometrioid endometrial carcinomas (EECs) represent the majority of sporadic cases of endometrial cancer and account for 70% to 80% of new cases [4]. Type 1 lesions arise in the background of endometrial hyperplasia and overall they are associated with a favorable prognosis. Unopposed estrogen stimulation has been proposed as the main factor associated with the development of this type of carcinomas [5].

On the contrary, type 2 lesions (NEECs) are less common, accounting for 10-20% of endometrial cases [6, 7]. They are not estrogen dependent and arise from a background of atrophic endometrium [4]. They are often high-grade carcinomas with poor prognosis, mainly of the papillary serous and clear-cell type [8].

Accumulating evidence over the past two decades has revealed the role of certain signaling pathways in endometrial carcinogenesis. Better understanding of the underlying oncogenic mechanisms may lead to discovery of novel therapeutic targets and ultimately increase the survival of those patients. One of the most important signaling pathways involved in gynecological carcinogenesis is the PI3K/AKT/mTOR pathway. Amplifications, mutations, and translocations, resulting in aberrant activation of this pathway, occur more frequently than any other pathway in cancer patients [9-13]. The present review will focus on the oncogenic role of mTOR signaling in endometrial tumors as well as potential therapeutic strategies related to this pathway.

2. Genetic Alterations of Endometrial Cancer

Apart from the morphologic and clinical features separating type 1 from type 2 ECs, they are further distinguished by specific genetic alterations [14]; EECs are characterized by microsatellite instability (MSI), somatic alterations within the PI3K pathway and the MAPK pathway, and mutations of CTNNB1 ([beta]-catenin) and ARID1A (BAF250a) genes. In contrast, NEECs often demonstrate aneuploidy, p53, and PPP2R1A mutations, p16 dysregulation, and significantly less frequent alterations within the PI3K pathway than in EECs.

Specifically, the PI3K-Akt signal transduction pathway is the most frequently altered biochemical pathway in EECs; more than 80% of endometrioid endometrial tumors had one or more somatic alterations affecting this pathway [15]. The primary negative regulator of the PI3K pathway is PTEN, a well-studied tumor suppressor gene. PTEN is located at chromosome 10q23 and encodes for a protein (phosphatase) with tyrosine kinase function. The PTEN product has both lipid and protein phosphatase activity. The lipid phosphatase activity causes cell cycle arrest at the [G.sub.2]/S checkpoint and inhibits PI3 phosphorylation by dephosphorylating PIP3 back to PIP2. This decreases intracellular PtdIns levels and affects the downstream Akt signal transduction pathway. The protein phosphatase activity of PTEN product has been found to inhibit cell spreading and migration. Thus, loss of PTEN activity may lead to aberrant cell growth and an escape from apoptosis [16] (Figure 1). PTEN inactivation can be due to either gene mutation, promoter methylation, or protein degradation, which lead to loss of expression, or to a lesser extent, loss of heterozygosity PTEN alterations are present in 20% of endometrial hyperplasia cases, in 55% of precancerous lesions, in 35-80% of EEC, and in 10% of NEECs [17-22]. PTEN mutations are likely an early event in endometrial carcinogenesis, as evidenced by its presence in precancerous lesions.

PIK3CA, another gene often mutated in various types of cancer, may also hold a role in the alteration of the phosphatidylinositol 3 kinase (PI3K)/Akt pathway in EC. PK3CA mutations appear in 25-36% of EECs and in 15% of NEECs and they often coincide with PTEN mutations [23-26]. A recent study explored whether mutations of the PI3K pathway, apart from PI3KCA and PTEN, were present in EC 15]. It has been reported from several groups a mutation rate of PIK3R1 up to 20%, significantly higher than any other lineage, demonstrating selective targeting in EC [15, 27, 28]. The PI3KR1 gene encodes for the PI3K regulatory subunit p85a. Several of its mutations are known to phosphorylate AKT, thus activating the downstream signaling pathway [29]. The PIK3R2 has also been established as a novel cancer gene. The mutation rate for PIK3R2 has been reported in up to 5% of ECs and several of those mutations have shown to exhibit gain of function [15]. Shoji et al. [30] detected the presence of AKT1 mutations in 2% of ECs tissue samples. These tumors did not demonstrate any other mutation in PIK3CA, PTEN, or K-Ras. The authors suggested that AKT1 mutations might be mutually exclusive with other PI3K-AKT activating alterations.

Although high AKT activity is well documented in endometrial adenocarcinomas, very little data exist on the role of the mTOR pathway in this type of cancer. In vivo data on the mTOR cascade components are also lacking. mTOR is the catalytic subunit of two biochemical distinct molecular complexes, mTORC1 and mTORC2. Activation of mTORC1 promotes ribosome biogenesis, increases translation rates and protein synthesis, and inhibits autophagy, thus affecting cell proliferation and cell survival [31]. All these functions are inhibited by rapamycin or rapamycin analogues [32]. Compared with mTORC1, the function of mTORC2 is less well studied, but it is known that mTORC2 activity regulates cytoskeleton organization and promotes activation of AKT (also known as protein kinase B) 33-35].

Darb-Esfahani et al. were among the first to demonstrate activation of p-mTOR and p-4EBP1 in human endometrial adenocarcinomas by immunohistochemistry [36]. Subsequently Shen et al. [37] demonstrated that mTORC2 activity is selectively upregulated in endometrial cancers, as evidenced by the overexpression of nuclear p-mTOR and p-Akt, as well as by the overexpression of VEGF-A isoform and PLD1 in malignant epithelium. The authors suggested that a rapamycin insensitive mTORC2 pathway could play a major role in endometrial tumorigenesis. Targeted therapies blocking the phospholipase D pathway and elements of the mTORC2 pathway could be effective against ECs. In addition, another study by Lu et al. demonstrated that dysregulation of mTOR in primary endometrial carcinomas may be achieved by loss of TSC2 and LKB1 expression (13% and 21%, resp.) [38].

Another important pathway in a variety of human cancers is the Ras/MARK pathway, which interacts with the PI3K pathway through the RAS proteins. This interaction may suggest a cooperation between the two pathways in order to determine functional outcomes. Somatic mutations of the KRAS gene are found in 18-28% of EECs [6,23, 39,40]. Constitutive activating mutations in K-Ras have been found more frequently in tumors with microsatellite instability (MSI), suggesting that both events may occur simultaneously before clonal expansion [41]. A MSI phenotype is marked by a high frequency of mutations at sites of short nucleotide repeats (microsatellites) within the genome. MSI is the result of unrepaired errors that arise during DNA replication and is detectable in almost 20% of endometrial tumors [42, 43]. In EC, KRAS mutations can coexist with mutations in PIK3CA, PIK3R1, and PTEN suggesting that KRAS mutations are not functionally redundant with PI3K pathway mutations [15,25, 29, 44].

3. Therapies Targeting the PI3K/Akt/mTOR Pathway

Our knowledge of the molecular pathways involved in endometrial carcinogenesis has led to the development of novel therapeutic agents that target these pathways. Several small-molecule inhibitors and monoclonal antibodies that interfere with mechanisms crucial for cancer development, such as angiogenesis, escaped from apoptosis, cell growth, and metastasis; are nowentering clinical trials [45,46]. Growing evidence suggests that genetic dysregulation of the PI3KAkt pathway results in the activation of downstream signaling pathways and is responsible for oncogenesis. Components of the Akt pathway may represent potential therapeutic targets [9, 46].

Akt is known to regulate various cellular pathways that promote cell survival, cell proliferation, angiogenesis, and invasion. In view of its antiapoptotic role, Akt overexpression in cancer cells might mediate resistance to radiation or chemotherapy [47]. Inhibition of phosphoinositide-3kinase (PI3K)/Akt signaling in endometrial carcinomas may be a promising target to enhance the efficacy of anticancer agents such as cisplatin and paclitaxel.

Evidence that the PI3K-Akt pathway can be targeted successfully for clinical use has been provided by studies that used rapamycin to inhibit mTOR, one of the numerous downstream Akt substrates [46,48]. Akt activity is frequently elevated in ovarian cancer and is closely associated with the upregulation of mTOR signaling [49]. Rapamycin, a highly specific mTOR inhibitor, arrests cells in the Gj phase and has shown antitumor activities in vivo as well as in vitro [50, 51]. Currently, mostly in vitro data have supported the antitumor effect of rapamycin and its derivatives in ovarian cancer [49, 52]. Other investigators have shown that rapamycin enhances the effect of cisplatin

and carboplatin in ovarian and breast cancer cells with mutant p53 [53, 54]. Similarly, rapamycin potentiates the effect of paclitaxel (inhibition of cellular proliferation, induction of apoptosis, and increased polymerization of tubulin) and cisplatin (inhibition of cell growth, induction of apoptosis, and increased expression of DNA mismatch repair proteins) in endometrial cancer cells [55, 56]. Also, recent clinical studies demonstrated the synergistic effect of rapalogs with chemotherapy in advanced gynecological malignancies and solid tumors [57-59].

Based on the biological rationale of targeting the mTOR pathway, mTOR inhibitors as single agent have entered clinical trials in endometrial cancer [46, 60] (Tables 1 and 2). An orally bioavailable derivative of rapamycin, RAD001 (Everolimus), has been shown to inhibit proliferation of tumor cell growth in vitro and in vivo [61-63]. In addition, Everolimus demonstrated encouraging results in a phase II clinical trial with previously treated patients with progressive or recurrent EeC [64]. In this report, 43% (12 out of 28 patients) of evaluable patients did not demonstrate disease progression at the time of first evaluation. However, the median duration of SD (stable disease) was 4.5 months and eleven patients discontinued treatment either due to toxicity (6 patients) or disease progression (5 patients). Although, mTOR inhibition demonstrated a clinical benefit, the authors believe that disease remission by receiving single agent therapy would be unlikely. Nonetheless, the interruption of a key component in a biologic pathway may be a reasonable approach for disease control.

Another mTOR inhibitor has also entered a phase II trial. Oza et al. [65] evaluated the activity of single-agent Temsirolimus (CC1-779) in women with chemotherapy-naive or chemotherapy-treated EC. Temsirolimus is a water-soluble ester of rapamycin and is administered by intravenous infusion. In the chemotherapy-naive group, 14% of evaluable patients had a partial response and 69% had stable disease; in the chemotherapy-treated group 4% of patients achieved partial response, while 48% had stable disease. Interestingly, there was no correlation between PTEN loss and other molecular markers of PI3K/Akt/mTOR pathway and clinical response. Temsirolimus is the most advanced of the rapalogs and after a positive phase III [66], the US Food and Drug Administration (FDA) approved it for the first line treatment of poor prognosis patients with advanced RCC.

Colombo et al. studied Ridaforolimus (AP23573), an intravenous mTOR inhibitor, in a phase II trial with recurrent EC. The investigators revealed that 7% of patients had partial response and 26% had stable disease [67]. Mackay et al. focused on endometrial cancer patients who did not receive chemotherapy. In this phase II study (n = 34) of Ridaforolimus 7.7% of the patients demonstrated partial response and 53% had stable disease [58].

As expected, however, single-agent treatment with rapamycin and its analogues activates negative feedback mechanisms leading to increased formation of mTORC2 complex, which not only phosphorylates and activates Akt [33, 69] but also promotes eIF4E Ser-209 phosphorylation, favoring its role in the initiation complex [70]. In order to bypass this problem, and induce the maximal inhibition of this pathway, Shoji et al. [71] examined the antitumor effect of combined PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001 (Everolimus), in endometrial cancer cells with one or more mutations in PTEN, K-Ras, and PIK3CA. They concluded that a combined PI3K/mTOR inhibition might be more efficacious than mTOR inhibition alone in women with EC [72]. Robust growth suppression of tumor cells with these agents indicates a promising therapeutic strategy. This novel therapeutic agent NVPBEZ235, which targets both PI3K and mTOR, has been shown to inhibit cell growth of cisplatin-sensitive as well as cisplatin-resistant human ovarian carcinoma cell lines [73, 74]. The effects of this combined PI3K/mTOR inhibitor have been attributed to the induction of cell cycle arrest, apoptosis as well as in its antiangiogenic properties [75-81].

Rapalogs combined to hormonal treatment for gynecological malignancies have also been evaluated in clinical trials [60]. In a phase II randomized clinical trial (n = 22) with previously treated patients Temsirolimus (25 mg IV weekly) combined with megestrol acetate (80 mg, twice a day (bid)) for three weeks, alternating in tamoxifen (20 mg bid) for three weeks was compared to Temsirolimus alone [82]. Due to high rate of thromboembolic events in the combination group, the study was terminated prematurely. The interim efficacy analysis demonstrated no significant differences in RR between the two groups.

Another study evaluated the combination of Everolimus (10mg/day, orally) and letrozole (2.5mg/day, orally) in patients (n = 28) pretreated with chemotherapy [83]. Preliminary data showed a CBR of 43% including four complete responses. In another phase II clinical trial involving patients with advanced endometrial carcinoma [84], Ridaforolimus (n = 64) given once daily (40 mg) for five days was compared to either hormonal therapy (n = 53) (medroxyprogesterone 200 mg/day or megestrol 60 mg/day) or chemotherapy (n = 13). Interim analysis demonstrated a median progression free survival of 3.6 months for Ridaforolimus compared to 1.9 months for those patients treated with hormones,. There was a significant difference in the rate of stable disease between the two groups (35% versus 17%, P = 0.02)

Other agents that can affect the PI3K/PTEN/Akt/mTOR signaling pathway have been developed and are currently under investigation in women with endometrial cancer. In a phase II trial of women with recurrent ovarian and endometrial cancer, MKC-1 (EntreMed), an oral cell cycle inhibitor, demonstrated a significant reduction of phospho-Akt [85]. Tanaka et al. examined the PI3K inhibitory activity of a novel agent, CH5132799, in ovarian, endometrial, breast, and prostate cancer cell lines, as well as in xenograft models [86]. CH5132799 is a selective class I PI3K inhibitor with a potent inhibitory activity against PI3K and its mutants. They were able to demonstrate an overall strong antiproliferative activity against the above tumors. In addition, CH5132799 in combination with trastuzumab had a synergistic effect without activation of the negative feedback loop of PI3K/Akt/mTOR signaling [86].

Apart from rapalogs, there is a growing interest in developing inhibitors for the catalytic domain mTOR of the complexes mTORC1 and mTORC2 [46]. A phase I clinical trial for the first oral small molecule mTORC1/mTORC2 inhibitor OSI-027 has been just completed; the study is multicenter and involves three different dosing schedules ( Identifier: NCT00698243) (Table 2).

4. Resistance of mTOR Inhibitors and Future Perspectives

Although clinical studies of rapalogs have shown promising results in renal-cell carcinoma [66, 89, 90], monotherapy with mTOR inhibitors, in other tumors, has shown limited efficacy due to the feedback activation of several survival signaling pathways [91-94]. Resistance to rapalogs could be explained by mechanisms involving the necessity of mT ORC1 to directly phosphorylate all the rapamycin-sensitive sites of its substrates, in vivo. One such mechanism, involves structural alteration of mTORC1 after a long-term rapamycin treatment [95]. This may depend on the site of raptor phosphorylation or the dissociation of mLST8 and PRAS40 from mTORC1. Differential phosphorylation by currently unknown kinases or transautophosphorylation may alter the structure of mTORC1. This would specifically recover the phosphorylation of some, but not all, of the substrates.

Another mechanism involves the effect of different binding affinities of mTORC1 substrates [95]. Specifically, it has been observed that S6K1 binds to mTORC1 much less efficiently than 4E-BP1 [96, 97]. In addition, 4E-BP1 T37/46, which are direct mTOR sites in vitro, are not rapamycin sensitive in vivo, whereas T389 on S6K1 is rapamycin-sensitive both in vivo and in vitro. This difference may explain why long-term rapamycin treatment recovers 4E-BP1 but not S6K1 phosphorylation.

Wang et al. suggested a critical role of Akt activation in the development of cell resistance to mTOR inhibitors [98]. In a rapamycin-resistant cell line p-Akt levels increased drastically and remained elevated for a long period after the removal of rapamycin. p-Akt levels returned to normal only after the sensitivity of the rapamycin-resistant cells to mTOR inhibitors was fully restored.

It seems that the survival signaling pathways, PI3K/Akt, MAPK/ERK, and Mnk/eIF4E, are important mediators of resistance to rapalogs. Inhibition of the mTORC1 with a rapalog induces a negative feedback loop activation of the survival pathways, leading to cell resistance to rapalogs [91].

Thus, the combination of rapalogs with other agents (hormonal, chemotherapy, etc.) or the development of novel PI3K and mTOR, combined inhibitors may prevent the feedback loop activation of the survival signaling pathways. Upon that, some mTOR/PI3K dual inhibitors have been developed such as the PI-103 [99] and the NVP-BEZ235 [75], both of which have demonstrated significant antitumor activity.

It has been suggested that another strategy to maximize the clinical effects of mTOR inhibitors would be selection of those patients more likely to respond to mTOR-targeted cancer therapy [46]. Investigation of reliable biomarkers that may predict tumor responses to rapalogs would be an interesting option. Slomovitz et al. [100]ina phase II clinical trial with Everolimus suggested that loss of PTEN in patients with EECs might predict response to the medication. In contrast, Yang et al. using Everolimus in a glioblastoma orthotopic xenograft test panel showed that PTEN loss does not predict response to the treatment [101]. In spite of the increasing interest, currently, there are no potential bio-markers that can aid in selecting patients who can benefit from mTOR inhibitors [102]. Thus, further work is essential in order to understand the biology of mTOR signaling and consequently to develop therapies for all suitable patients on a personalized basis. Additionally, important issue is a therapeutic option that can be economical sustained. Oral rapamycin (Sirolimus), which has been shown to exhibit the same toxicities as its derivatives, it has become widely available after the expiration of the patent in 2013 [103]. The use of the original compound may limit the cost compared with the rest of mTOR inhibitors.

5. Conclusions

As discussed above, a link between the mTOR pathway and endometrioid endometrial cancer is clearly evident and most of its upstream and downstream regulators are directly implicated in cancer initiation and progression. Improved understanding of the molecular mechanisms involved in endometrial carcinogenesis has led to the identification and development of molecular target therapies. Encouraging results from in vitro studies and early stage clinical trials of first generation mTOR and PI3K inhibitors in gynecological cancers have recently become available. Moving forward, future phase III studies should evaluate whether rapalogs, either as monotherapy or in combination with other agents, could improve survival in patients who have disease resistant to first-line therapies. 10.1155/2014/709736

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


[1] J. Ferlay, H.-R. Shin, F. Bray, D. Forman, C. Mathers, and D. M. Parkin, "Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008," International Journal of Cancer, vol. 127, no. 12, pp. 2893-2917, 2010.

[2] Cancer Facts and Figures, American Cancer Society, 2013.

[3] A. Doll, M. Abal, M. Rigau et al., "Novel molecular profiles of endometrial cancer-new light through old windows," Journal of Steroid Biochemistry and Molecular Biology, vol. 108, no. 3-5, pp. 221-229, 2008.

[4] J. V. Bokhman, "Two pathogenetic types of endometrial carcinoma," Gynecologic Oncology, vol. 15, no. 1, pp. 10-17, 1983.

[5] N. Potischman, R. N. Hoover, L. A. Brinton et al., "Case-control study of endogenous steroid hormones and endometrial cancer," Journal of the National Cancer Institute, vol. 88, no. 16, pp. 1127-1135, 1996.

[6] S. F. Lax, B. Kendall, H. Tashiro, R. J. Slebos, and L. Hedrick, "The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways," Cancer, vol. 88, no. 4, pp. 814-824, 2000.

[7] F.-S. Liu, "Molecular carcinogenesis of endometrial cancer," Taiwanese Journal of Obstetrics and Gynecology, vol. 46, no. 1, pp. 26-32, 2007

[8] M. K. Oehler, A. Brand, and G. V. Wain, "Molecular genetics and endometrial cancer," Journal of the British Menopause Society, vol. 9, no. 1, pp. 27-31, 2003.

[9] B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, and G. B. Mills, "Exploiting the PI3K/AKT pathway for cancer drug discovery," Nature Reviews Drug Discovery, vol. 4, no. 12, pp. 988-1004, 2005.

[10] I. Vivanco and C. L. Sawyers, "The phosphatidylinositol 3-kinase-AKT pathway in human cancer," Nature Reviews Cancer, vol. 2, no. 7, pp. 489-501, 2002.

[11] A. Bellacosa, C. C. Kumar, A. D. Cristofano, and J. R. Testa, "Activation of AKT kinases in cancer: implications for therapeutic targeting," Advances in Cancer Research, vol. 94, no. 1, pp. 29-86, 2005.

[12] B. D. Manning and L. C. Cantley, "AKT/PKB signaling: navigating downstream," Cell, vol. 129, no. 7, pp. 1261-1274, 2007

[13] J. A. Engelman, J. Luo, and L. C. Cantley, "The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism," Nature Reviews Genetics, vol. 7, no. 8, pp. 606-619, 2006.

[14] J. L. Hecht and G. L. Mutter, "Molecular and pathologic aspects of endometrial carcinogenesis," Journal of Clinical Oncology, vol. 24, no. 29, pp. 4783-4791, 2006.

[15] L. W. Cheung et al., "High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability," Cancer Discovery, vol. 1, no. 2, pp. 170-185, 2011.

[16] H. Wu, V. Goel, and F. G. Haluska, "PTEN signaling pathways in melanoma," Oncogene, vol. 22, no. 20, pp. 3113-3122, 2003.

[17] H. Sun, T. Enomoto, M. Fujita et al., "Mutational analysis of the PTEN gene in endometrial carcinoma and hyperplasia," American Journal of Clinical Pathology, vol. 115, no. 1, pp. 32-38, 2001.

[18] Y. Kanamori, J. Kigawa, H. Itamochi et al., "Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma," Clinical Cancer Research, vol. 7, no. 4, pp. 892895, 2001.

[19] M. R. Quddus, B. A. Ologun, C. J. Sung, M. M. Steinhoff, and W. D. Lawrence, "Utility of PTEN expression of endometrial "surface epithelial changes" and underlying atypical endometrial hyperplasia," International Journal of Gynecological Pathology, vol. 28, no. 5, pp. 471-476, 2009.

[20] D. Kong, A. Suzuki, T. T. Zou et al., "PTEN1 is frequently mutated in primary endometrial carcinomas," Nature Genetics, vol. 17, no. 2, pp. 143-144, 1997

[21] G. L. Mutter, "PTEN, a protean tumor suppressor," American Journal of Pathology, vol. 158, no. 6, pp. 1895-1898, 2001.

[22] N. Bansal, V. Yendluri, and R. M. Wenham, "The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies," Cancer Control, vol. 16, no. 1, pp. 8-13, 2009.

[23] A. Velasco, E. Bussaglia, J. Pallares et al., "PIK3CA gene mutations in endometrial carcinoma. Correlation with PTEN and K-RAS alterations," Human Pathology, vol. 37, no. 11, pp. 1465-1472, 2006.

[24] M. P. Hayes, W. Douglas, and L. H. Ellenson, "Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma," Gynecologic Oncology, vol. 113, no. 3, pp. 370-373, 2009.

[25] K. Oda, D. Stokoe, Y. Taketani, and F. McCormick, "High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma," Cancer Research, vol. 65, no. 23, pp. 10669-10673, 2005.

[26] K. Oda, J. Okada, L. Timmerman et al., "PIK3CA cooperates with other phosphatidylinositol B'-kinase pathway mutations to effect oncogenic transformation," Cancer Research, vol. 68, no. 19, pp. 8127-8136, 2008.

[27] "Comprehensive genomic characterization defines human glioblastoma genes and core pathways," Nature, vol. 455, no. 7216, pp. 1061-1068, 2008.

[28] B. S. Jaiswal, V. Janakiraman, N. M. Kljavin et al., "Somatic mutations in p85[alpha] promote tumorigenesis through class IA PI3K activation," Cancer Cell, vol. 16, no. 6, pp. 463-474, 2009.

[29] M. E. Urick, M. L. Rudd, A. K. Godwin, D. Sgroi, M. Merino, and D. W. Bell, "PIK3R1 (p85[alpha]) is somatically mutated at high frequency in primary endometrial cancer," Cancer Research, vol. 71, no. 12, pp. 4061-4067, 2011.

[30] K. Shoji, K. Oda, S. Nakagawa et al., "The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas," British Journal of Cancer, vol. 101, no. 1, pp. 145-148, 2009.

[31] D.-H. Kim, D. D. Sarbassov, S. M. Ali et al., "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery," Cell, vol. 110, no. 2, pp. 163-175, 2002.

[32] D. D. Sarbassov, S. M. Ali, and D. M. Sabatini, "Growing roles for the mTOR pathway," Current Opinion in Cell Biology, vol. 17, no. 6, pp. 596-603, 2005.

[33] D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, "Phosphorylation and regulation of Akt/PKB by the rictormTOR complex," Science, vol. 307, no. 5712, pp. 1098-1101, 2005.

[34] E. Jacinto, R. Loewith, A. Schmidt et al., "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive," Nature Cell Biology, vol. 6, no. 11, pp. 1122-1128, 2004.

[35] D. D. Sarbassov, S. M. Ali, D.-H. Kim et al., "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton," Current Biology, vol. 14, no. 14, pp. 1296-1302, 2004.

[36] S. Darb-Esfahani, A. Faggad, A. Noske et al., "Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro," Journal of Cancer Research and Clinical Oncology, vol. 135, no. 7, pp. 933-941, 2009.

[37] Q. Shen, M. L. Stanton, W. Feng et al., "Morphoproteomic analysis reveals an overexpressed and constitutively activated phospholipase D1-mTORC2 pathway in endometrial carcinoma," International Journal of Clinical and Experimental Pathology, vol. 4, no. 1, pp. 13-21, 2011.

[38] K. H. Lu, W. Wu, B. Dave et al., "Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma," Clinical Cancer Research, vol. 14, no. 9, pp. 2543-2550, 2008.

[39] S. Kang, S. S. Seo, H. J. Chang, C. W. Yoo, S. Y. Park, and S. M. Dong, "Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma," International Journal of Gynecological Cancer, vol. 18, no. 6, pp. 1339-1343, 2008.

[40] T. Enomoto, M. Inoue, A. O. Perantoni et al., "K-ras activation in premalignant and malignant epithelial lesions of the human uterus," Cancer Research, vol. 51, no. 19, pp. 5308-5314, 1991.

[41] H. Lagarda et al., "K-ras mutations in endometrial carcinomas with microsatellite instability" The Journal of Pathology, vol. 193, no. 2, pp. 193-199, 2001.

[42] K. Kobayashi, S. Sagae, R. Kudo, H. Saito, S. Koi, and Y. Nakamura, "Microsatellite instability in endometrial carcinomas: frequent replication errors in tumors of early onset and/or of poorly differentiated type," Genes Chromosomes and Cancer, vol. 14, no. 2, pp. 128-132, 1995.

[43] R. T. Burks, T. D. Kessis, K. R. Cho, and L. Hedrick, "Micro-satellite instability in endometrial carcinoma," Oncogene, vol. 9, no. 4, pp. 1163-1166, 1994.

[44] M. L. Rudd, J. C. Price, S. Fogoros et al., "A unique spectrum of somatic PIK3CA (p110[alpha]) mutations within primary endometrial carcinomas," Clinical Cancer Research, vol. 17, no. 6, pp. 1331-1340, 2011.

[45] D. Hanahan and R. A. Weinberg, "The hallmarks of cancer," Cell, vol. 100, no. 1, pp. 57-70, 2000.

[46] T. A. Yap, M. D. Garrett, M. I. Walton, F. Raynaud, J. S. de Bono, and P. Workman, "Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises," Current Opinion in Pharmacology, vol. 8, no. 4, pp. 393-412, 2008.

[47] J. Q. Cheng, C. W. Lindsley, G. Z. Cheng, H. Yang, and S. V. Nicosia, "The Akt/PKB pathway: molecular target for cancer drug discovery," Oncogene, vol. 24, no. 50, pp. 7482-7492, 2005.

[48] T. A. Yap, C. P. Carden, and S. B. Kaye, "Beyond chemotherapy: targeted therapies in ovarian cancer," Nature Reviews Cancer, vol. 9, no. 3, pp. 167-181, 2009.

[49] D. A. Altomare, Q. W. Hui, K. L. Skele et al., "AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth," Oncogene, vol. 23, no. 34, pp. 5853-5857, 2004.

[50] M. B. Dilling, P. Dias, D. N. Shapiro, G. S. Germain, R. K. Johnson, and P. J. Houghton, "Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor," Cancer Research, vol. 54, no. 4, pp. 903-907, 1994.

[51] D. P. Houchens, A. A. Ovejera, S. M. Riblet, and D. E. Slagel, "Human brain tumor xenografts in nude mice as a chemotherapy model," European Journal of Cancer and Clinical Oncology, vol. 19, no. 6, pp. 799-805, 1983.

[52] D. Aguirre, P. Boya, D. Bellet et al., "Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma," Apoptosis, vol. 9, no. 6, pp. 797-805, 2004.

[53] Y. Shi, A. Frankel, L. G. Radvanyi, L. Z. Penn, R. G. Miller, and G. B. Mills, "Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro," Cancer Research, vol. 55, no. 9, pp. 1982-1988, 1995.

[54] W. H. Mondesire, W. Jian, H. Zhang et al., "Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells," Clinical Cancer Research, vol. 10, no. 20, pp. 7031-7042, 2004.

[55] V. L. Bae-Jump, C. Zhou, J. F. Boggess, and P. A. Gehrig, "Synergistic effect of rapamycin and cisplatin in endometrial cancer cells," Cancer, vol. 115, no. 17, pp. 3887-3896, 2009.

[56] A. Shafer, C. Zhou, P. A. Gehrig, J. F. Boggess, and V. L. Bae-Jump, "Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis," International Journal of Cancer, vol. 126, no. 5, pp. 1144-1154, 2010.

[57] C. Kollmannsberger, H. Hirte, L. L. Siu et al., "Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179)," Annals of Oncology, vol. 23, no. 1, pp. 238-244, 2012.

[58] M. Campone, V. Levy, E. Bourbouloux et al., "Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours," British Journal of Cancer, vol. 100, no. 2, pp. 315-321, 2009.

[59] S. M. Temkin, S. D. Yamada, and G. F. Fleming, "A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies," Gynecologic Oncology, vol. 117, no. 3, pp. 473-476, 2010.

[60] I. Diaz-Padilla, I. Duran, B. A. Clarke, and A. M. Oza, "Biologie rationale and elinieal activity of mTOR inhibitors in gynecologieal cancer," Cancer Treatment Reviews, 2012.

[61] P. K. Majumder, P. G. Febbo, R. Bikoff et al., "mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways," Nature Medicine, vol. 10, no. 6, pp. 594-601, 2004.

[62] A. Boulay, S. Zumstein-Mecker, C. Stephan et al., "Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells," Cancer Research, vol. 64, no. 1, pp. 252-261, 2004.

[63] I. Beuvink, A. Boulay, S. Fumagalli et al., "The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation," Cell, vol. 120, no. 6, pp. 747-759, 2005.

[64] B. M. Slomovitz, K. H. Lu, T. Johnston et al., 'A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma," Cancer, vol. 116, no. 23, pp. 5415-5419, 2010.

[65] A. M. Oza, L. Elit, M.-S. Tsao et al., "Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group," Journal of Clinical Oncology, vol. 29, no. 24, pp. 3278-3285, 2011.

[66] G. Hudes, M. Carducci, P. Tomczak et al., "Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma," The New England Journal of Medicine, vol. 356, no. 22, pp. 2271-2281, 2007.

[67] N. Colombo, S. McMeekin, P. Schwartz et al., "A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer," Journal of Clinical Oncology, vol. 25, 2007, [abstract].

[68] H. Mackay, S. Welch, M. S. Tsao et al., "Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192," Journal of Clinical Oncology, vol. 29, 2011.

[69] K. E. O'Reilly, F. Rojo, Q.-B. She et al., "mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt," Cancer Research, vol. 66, no. 3, pp. 1500-1508, 2006.

[70] X. Wang, P. Yue, C.-B. Chan et al., "Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinasedependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation," Molecular and Cellular Biology, vol. 27, no. 21, pp. 7405-7413, 2007

[71] K. Shoji, K. Oda, T Kashiyama et al., "Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas," PLoS ONE, vol. 7, no. 5, Article ID e37431, 2012.

[72] P. M. Bhende, S. I. Park, M. S. Lim, D. P. Dittmer, and B. Damania, "The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma," Leukemia, vol. 24, no. 10, pp. 1781-1784, 2010.

[73] T Muranen, L. M. Selfors, D. T Worster et al., "Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells," Cancer Cell, vol. 21, no. 2, pp. 227-239, 2012.

[74] C. Santiskulvong, G. E. Konecny, M. Fekete et al., "Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma," Clinical Cancer Research, vol. 17, no. 8, pp. 2373-2384, 2011.

[75] S. M. Maira, F. Stauffer, J. Brueggen et al., "Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity," Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 1851-1863, 2008.

[76] A. M. Roccaro, A. Sacco, E. N. Husu et al., "Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia," Blood, vol. 115, no. 3, pp. 559-569, 2010.

[77] V Serra, B. Markman, M. Scaltriti et al., "NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations," Cancer Research, vol. 68, no. 19, pp. 8022-8030, 2008.

[78] T.-J. Liu, D. Koul, T LaFortune et al., "NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas," Molecular Cancer Therapeutics, vol. 8, no. 8, pp. 2204-2210, 2009.

[79] D. W. McMillin, M. Ooi, J. Delmore et al., "Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVPBEZ235," Cancer Research, vol. 69, no. 14, pp. 5835-5842, 2009.

[80] R. Marone, D. Erhart, A. C. Mertz et al., "Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors," Molecular Cancer Research, vol. 7, no. 4, pp. 601-613, 2009.

[81] P. Baumann, S. Mandl-Weber, F. Oduncu, and R. Schmidmaier, "The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma," Experimental Cell Research, vol. 315, no. 3, pp. 485-497, 2009.

[82] G. F. Fleming, V. L. Filiaci, P. Hanjani et al., "Hormone therapy plus temsirolimus for endometrial carcinoma (EC): Gynecologic Oncology Group trial 248," Journal of Clinical Oncology, vol. 29, 2011.

[83] B. M. Slomovitz, J. Brown, T A. Johnston et al., "A phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma," Journal of Clinical Oncology, vol. 29, 2011.

[84] A. Oza, A. Poveda, A. R. Clamp et al., "A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotherapy (C) in female adult patients with advanced endometrial carcinoma," Journal of Clinical Oncology, vol. 29, 2011.

[85] H. Hirte, L. Kaizer, H. Mackay et al., "Phase II study of MKC-1 in patients with metastatic or resistant epithelial ovarian cancer or advanced endometrial cancer," Journal of Clinical Oncology, vol. 27, no. 5577, 2009, abstract no. 5577

[86] H. Tanaka, M. Yoshida, H. Tanimura et al., "The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations," Clinical Cancer Research, vol. 17, no. 10, pp. 3272-3281, 2011.

[87] T Yoshioka, S. Yogosawa, T. Yamada, J. Kitawaki, and T. Sakai, "Combination of a novel HDAC inhibitor OBP-801/YM753 and a PI3K inhibitor LY294002 synergistically induces apoptosis in human endometrial carcinoma cells due to increase of Bim with accumulation of ROS," Gynecologic Oncology, vol. 129, no. 2, pp. 425-432, 2013.

[88] A. M. Oza, L. Elit, J. Biagi et al., "Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer--NCIC IND 160," Journal of Clinical Oncology, vol. 24, 2006, abstract no. 3003.

[89] R. J. Amato, J. Jac, S. Giessinger, S. Saxena, and J. P. Willis, "A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer," Cancer, vol. 115, no. 11, pp. 2438-2446, 2009.

[90] R. J. Motzer, B. Escudier, S. Oudard et al., "Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlledphase IIItrial," The Lancet, vol. 372,no. 9637, pp. 449-456, 2008.

[91] X. Wang and S.-Y. Sun, "Enhancing mTOR-targeted cancer therapy," Expert Opinion on Therapeutic Targets, vol. 13, no. 10, pp. 1193-1203, 2009.

[92] J. LoPiccolo, G. M. Blumenthal, W. B. Bernstein, and P. A. Dennis, "Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations," Drug Resistance Updates, vol. 11, no. 1-2, pp. 32-50, 2008.

[93] G. G. Chiang and R. T. Abraham, "Targeting the mTOR signaling network in cancer," Trends in Molecular Medicine, vol. 13, no. 10, pp. 433-442, 2007.

[94] R. T. Abraham and J. J. Gibbons, "The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy," Clinical Cancer Research, vol. 13, no. 11, pp. 3109-3114, 2007.

[95] A. Y. Choo and J. Blenis, "Not all substrates are treated equally Implications for mTOR, rapamycin-resistance and cancer therapy," Cell Cycle, vol. 8, no. 4, pp. 567-572, 2009.

[96] S. S. Schalm and J. Blenis, "Identification of a conserved motif required for mTOR signaling," Current Biology, vol. 12, no. 8, pp. 632-639, 2002.

[97] S. S. Schalm, D. C. Fingar, D. M. Sabatini, and J. Blenis, "TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function," Current Biology, vol. 13, no. 10, pp. 797-806, 2003.

[98] X. Wang, P Yue, A. K. Young, H. Fu, F. R. Khuri, and S.Y. Sun, "Enhancing mammalian target of rapamycin (mTOR)targeted cancer therapy by preventing mTOR/raptor inhibition initiated, mTOR/rictor-independent Akt activation," Cancer Research, vol. 68, no. 18, pp. 7409-7418, 2008.

[99] Q.-W. Fan, Z. A. Knight, D. D. Goldenberg et al., "A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma," Cancer Cell, vol. 9, no. 5, pp. 341-349, 2006.

[100] B. Slomovitz, K. H. Lu, T Johnston et al., "A phase II study of oral mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), in patients with recurrent endometrial carcinoma (EC)," J Clin Oncol, vol. 26, no. 15S, 2008.

[101] L. Yang, M. J. Clarke, B. L. Carlson et al., "PTEN loss does not predict for response to RAD001 (everolimus) in a glioblastoma orthotopic xenograft test panel," Clinical Cancer Research, vol. 14, no. 12, pp. 3993-4001, 2008.

[102] C. Delbaldo, S. Albert, C. Dreyer et al., "Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors," Targeted Oncology, vol. 6, no. 2, pp. 119-124, 2011.

[103] E. E. W. Cohen, "mTOR: the mammalian target of replication," Journal of Clinical Oncology, vol. 26, no. 3, pp. 348-349, 2008.

Athanasia Pavlidou (1) and Nikos F. Vlahos (1,2)

(1) Second Department of Obstetrics and Gynecology, University of Athens Medical School, Aretaieion University Hospital, 76 Vas. Sofias Avenue, 11527Athens, Greece

(2) Department of Gynecology and Obstetrics, The Johns Hopkins Hospital School of Medicine, Baltimore, MD 21287, USA

Correspondence should be addressed to Athanasia Pavlidou;

Received 30 August 2013; Accepted 9 October 2013; Published 12 January 2014

Academic Editors: D. H. Dinh, E. K. Han, D. G. Mutch, and E. O. Pettersen

TABLE 1: PI3k/Akt/mTOR inhibitors in preclinical and clinical

Drug                                     Target kinase      Clinical

Preclinical studies
  CH5132799                                  PI3K
  NVP-BEZ235 + RAD001                      PI3K/mTOR
  LY294002 + OBP-801/YM753                 PI3K/HDAC
Published studies and abstracts
  Temsirolimus                               mTOR           Phase II
  Ridaforolimus                              mTOR           Phase II
  Everolimus                                 mTOR           Phase II
  MKC-1                                                     Phase II
  Temsirolimus + megestrol + tamoxifen       mTOR           Phase II
  Everolimus + letrozole                     mTOR           Phase II
  Ridaforolimus versus                       mTOR           Phase II
  medroxyprogesterone versus

Drug                                       N      PR         SD

Preclinical studies
  NVP-BEZ235 + RAD001
  LY294002 + OBP-801/YM753
Published studies and abstracts
  Temsirolimus                            19     7-26%     44-69%
  Ridaforolimus                          45,34    7%       26-53%
  Everolimus                              35      57%       43%
  MKC-1                                    9     55.5%     44.4%
  Temsirolimus + megestrol + tamoxifen    22
  Everolimus + letrozole                  28
  Ridaforolimus versus                    53             35% versus
  medroxyprogesterone versus                                17%

Drug                                          PFS         References

Preclinical studies
  CH5132799                                                  [86]
  NVP-BEZ235 + RAD001                                        [72]
  LY294002 + OBP-801/YM753                                   [87]
Published studies and abstracts
  Temsirolimus                             4.3 months      [65, 88]
  Ridaforolimus                             16 weeks       [67, 68]
  Everolimus                                >8 weeks         64]
  MKC-1                                    1.8 weeks         [85]
  Temsirolimus + megestrol + tamoxifen                       [82]
  Everolimus + letrozole                    >8 weeks         83]
  Ridaforolimus versus                   3.6 versus 1.9      [84]
  medroxyprogesterone versus                 months

* N: number of patients; PFS: progression free survival; PR: partial
response; SD: stable disease.

TABLE 2: PI3K/Akt/mTOR inhibitors in ongoing trials.

Ongoing trials                Target kinase    Clinical trial ph

PF-04691502 + PF-05212384       PI3K/mTOR          Phase II
XL147                             PI3K             Phase II
MK2206                             Akt             Phase II
Temsirolimus + pegylated          mTOR              Phase I
  liposomal Doxorubicin
Ridaforolimus or progestin        mTOR             Phase II
  or chemotherapy
Ridaforolimus + paclitaxel        mTOR              Phase I
  + carboplatin
Temsirolimus + bevacizumab     mTOR + VEGF         Phase II
OSI-027                      mTORC1 + mTORC2       Phase II

Ongoing trials                 ise N        PFS        ClinicalTrials.
                                                       gov identifier

PF-04691502 + PF-05212384    Recruiting                 NCT01420081
XL147                            65       6 months      NCT01013324
MK2206                       Recruiting                 NCT01307631
Temsirolimus + pegylated     Recruiting                 NCT00982631
  liposomal Doxorubicin
Ridaforolimus or progestin      130                     NCT00739830
  or chemotherapy
Ridaforolimus + paclitaxel   Recruiting                 NCT01256268
  + carboplatin
Temsirolimus + bevacizumab   Recruiting                 NCT01010126
OSI-027                         128                     NCT00698243

* N: number of patients; PFS: progression free survival.
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Author:Pavlidou, Athanasia; Vlahos, Nikos F.
Publication:The Scientific World Journal
Article Type:Report
Date:Jan 1, 2014
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