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Gastric cancer remains one of the most common types of cancer worldwide, and most patients present with advanced disease. Sixty percent of these patients eventually relapse after curative surgical resection, and combination chemotherapy regimens only provide limited survival benefits. Mammalian target of rapamycin (mTOR) is a new target of cancer therapies. Preclinical data suggest that the suppression of the mTOR pathway inhibits the progression of gastric cancer in vitro and in animal models. In clinical trials, the mTOR inhibitor, everolimus, was well tolerated in phase I/II studies on patients with metastatic gastric cancer. The efficacy of everolimus was promising in a phase II clinical trial, but in a recently published phase III clinical trial everolimus monotherapy do not significantly improve the overall survival of patients with advanced gastric cancer who had been previously treated with one or two lines of systemic chemotherapy. Phosphoinositide 3-kinase/mTOR dual inhibitors have not yet entered early-stage clinical trials in patients with advanced gastric cancer. Further studies are needed to establish the role of mTOR inhibitors for the treatment of gastric cancer.
Key words: Gastric cancer; mTOR inhibitors; everolimus
Gastric cancer is one of the most common types of cancer around the world. A total of 989,600 new cases of stomach cancer and 738,000 deaths are estimated to have occurred in 2008, accounting for 8% of the total cases of cancer and 10% of the total cancer deaths . The highest incidence rates are found in Eastern Asia, Eastern Europe, and South America. In China, the age-standardized incidence rates were 41.9 (per 100,000) for males and 19.5 for females in 2000 and 37.1 for males and 17.4 for females in 2005. The age-standardized mortality rates were 32.7 (per 100,000) for males and 15.0 for females in 2000 and 28.8 for males and 13.3 for females in 2005. In 2005, 300,000 deaths and 400,000 new cases of gastric cancer were reported, making gastric cancer the third most common cancer .
Surgery is the prinicpal treatment for gastric cancer. Gastric cancer, when detected early, has excellent prognosis after surgical treatment, with a 5-year survival rate that is > 90% ; however, most patients present with advanced disease and the long-term survival is poor for these cases. These cases do not demonstrate a survival advantage even when an extensive lymphadenectomy is performed . Sixty percent of patients who present with advanced disease eventually relapse after curative surgical resection . Systemic chemotherapy has been extensively evaluated in patients with resectable and unresectable gastric cancer. At present, the most common agents are fluorouracil (FU) and its derivatives, including taxanes, irinotecan, and platinum derivatives. Combination chemotherapy regimens have been shown to prolong the median overall survival (OS), but generally survival is less than 1 year [9-12]. The poor long-term outcome of patients with gastric cancer suggests a need for novel targeted agents, which may improve the clinical prognosis . This review focuses on the relevance of the mammalian target of rapamycin (mTOR) pathway in gastric cancer and the clinical results of using mTOR inhibitors to treat patients with gastric cancer.
Mechanistic action of mTOR inhibitors
Inhibition of the mTOR pathway is a new therapy for the treatment of various human cancers. mTOR is a critical regulator of cell proliferation, metabolism, and protein synthesis via the phosphoinositide 3-kinase (PI3K)-Akt pathway. Signals from growth factor receptors activate PI3K, resulting in Akt activation and, eventually, activation of the components of mTOR that are centrally located downstream. Mutations in the upstream components of the mTOR signaling pathway result in inappropriate mTOR activation , thus promoting tumor progression. In a genetic analysis of patients with esophageal cancer, Akt mutations were associated with an increased risk of recurrence after chemotherapy, and mutations to the phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt, were associated with a decreased risk of recurrence, possibly due to increased PTEN expression . Mutations to PI3K have also been noted . Regardless of the mechanism of aberrant mTOR activation, preclinical studies suggest that tumors with mutations in the mTOR pathway are uniquely susceptible to mTOR inhibitor therapy . It has been demonstrated that Akt, mTOR, and S6K1 are phosphorylated (i.e., activated) in most types of cancer. Activation of PI3K/Akt/mTOR is essential for the proliferation and survival of malignancies. The inhibition of mTOR signaling can abrogate the cellular response to the activation of growth factor receptors. The mTOR pathway has frequently been shown to be dysregulated in many types of cancers, including gastric cancers .
Preclinical data on mTOR inhibition in human gastric cancer
Samples from gastric cancer patients demonstrate mTOR expression and activation, and phosphorylated mTOR (p-mTOR) is positively correlated with tumor progression and poor survival in patients with gastric cancer. In 1072 gastric cancer specimens, the total expression levels of mTOR and p-mTOR were analyzed using immunohistochemistry and confirmed by Western blot analysis. It was found that p-mTOR overexpression is correlated with total mTOR overexpression and p-mTOR overexpression was indicated as an independent prognostic factor . In pT2b gastric cancer, p-mTOR expression is associated with extensive lymph node metastasis and poor disease-free survival . In 109 patients with gastric adenocarcinoma, the expression levels of p-mTOR and phosphorylated Akt (p-Akt) in the cytoplasm and nucleus were analyzed, and cytoplasmic p-mTOR expression was associated with significantly poorer relapse-free survival and OS .
Preclinical studies performed using gastric cancer mouse models also suggest that mTOR is a potential therapeutic target. Everolimus reduced peritoneal dissemination in a gastric cancer cell line in a mouse model . In combination with cyclophosphamide, everolimus exhibited synergistic antitumor activity in gastric cancer xenografts .Â Rapamycin has also been shown to enhance the cytotoxic effects of 5-FU, docetaxel, and cisplatin in preclinical models .
Clinical trials on the efficacy of everolimus in patients with metastatic gastric cancer
Everolimus is the only mTOR inhibitor that has been investigated in clinical trials using patients with gastric cancer. In a phase I dose-escalation trail , RAD001 was continuously administered once daily over the course of a 28-day cycle. Nine Japanese patients were recruited in a 3 Ã- 3 design study, where three successive cohorts were treated with RAD001 at a dose of 2.5, 5.0, or 10.0 mg/day, respectively. Of seven patients whose tumor response was assessed, tumor shrinkage was observed in two patients treated with 10.0 mg/day RAD001. The most common adverse effects (AEs), regardless of grade, included thrombocytopenia (56%), leukopenia (33%), anorexia (44%), and rash (44%). Grade 3 and 4 toxicities were only noted at the dose of 10 mg/day; toxicity was not noted in the first cycle but did not qualify as DLTs. One patient with advanced esophageal carcinoma developed grade 3 fatigue and stomatitis. One patient with colorectal cancer developed grade 3 hyperglycemia.
The efficacy of everolimus is supported by the results of a phase II clinical trial. This was an open-label, single-arm, multicenter, proof-of-concept study that enrolled patients with advanced gastric adenocarcinoma who had received one or two prior chemotherapy regimens . All patients were treated with 10 mg/day oral everolimus that was administered over the course of a continuous 28-day cycle. The primary study endpoint was the disease control rate (DCR). Among 53 evaluated patients, no complete or partial response was observed, but a decrease in tumor size from baseline was observed in 45% of patients. DCR was 56.0%, and the median PFS was 2.7 months. After a median follow-up time of 9.6 months, the median OS was 10.1 months. The major AEs of everolimus were mostly grade 1 or 2 in severity. The most common AEs included stomatitis (73.6%), anorexia (52.8%), fatigue (50.9%), rash (45.3%), nausea (32.1%), peripheral edema (22.6%), diarrhea (20.8%), and pruritus (18.9%). Grade 3 AEs presented in 20 patients (37.7%), including anemia (11.3%), hyponatremia (9.4%), increased Î³-glutamyltransferase (7.5%), lymphopenia (7.5%), fatigue (5.7%), stomatitis (5.7%), anorexia (5.7%), abnormal hepatic function (5.7%), hyperglycemia (3.8%), hypophosphatemia (3.8%), and ileus (3.8%). Grade 4 AEs were suspected as being treatment related and were reported in four patients; one patient presented with tumor hemorrhage, increased Î³-glutamyltransferase, lymphopenia, and cerebral infarction, respectively. This clinical trial indicates that everolimus monotherapy is a promising treatment for patients with previously treated advanced gastric cancer.
Phase III clinical trial data on the effectiveness of everolimus for the treatment of gastric cancer are now available. The results were presented at the 2012 ASCO GI meeting, including the results of GRANITE-1, a randomized, double-blind, multicenter, phase III study . Patients with confirmed advanced gastric cancer and disease progression after one or two lines of systemic chemotherapy were randomized (in a 2:1 ratio) and received 10 mg/day oral everolimus plus best supportive care (BSC) or placebo (PBO) plus BSC. A total of 656 patients from 23 countries were enrolled from July 2009 through December 2010; 439 patients received everolimus and 217 received PBO. The majority of these patients were men (73.6%) in Asia (55.3%), and 47.7% had received one previous line of chemotherapy and 50.6% had undergone a gastrectomy. The median OS was 5.39 months for everolimus versus 4.34 months for PBO. The Median PFS, as assessed by the local investigator, was 1.68 months for everolimus versus 1.41 months for PBO. The 6-month PFS estimates were 12.0% for EVE and 4.3% for PBO. The OS and PFS results were consistent across the various subgroups. The objective response rate (ORR) was 4.5% for everolimus versus 2.1% for PBO. The most common grade 3/4 AEs included anemia (16.0% for everolimus vs. 12.6% for PBO), decreased appetite (11.0% vs. 5.6%), and fatigue (7.8% vs. 5.1%). These results indicate that everolimus monotherapy does not significantly improve OS in patients with advanced gastric cancer who have been previously treated with one or two lines of systemic chemotherapy.
mTOR/PI3K dual inhibitors
It is now recognized that mTOR inhibitors do not sufficiently achieve robust anticancer effects, at least when these agents are employed in monotherapy regimens, however mTOR/PI3K dual inhibitors (TPdIs) have been developed. Two preclinical research studies have evaluated the in vivo antitumor activities of mTOR/PI3K inhibitors against gastric cancer cells. In xenograft mouse models, BEZ235 only showed a significant dose-dependent antitumor response in NCI-N87 xenografts. BEZ235 did not impair tumor growth despite mTOR/PI3K target regulation in other xenograft mouse models . PI103-enhanced 5-FU sensitivity was identified in three out of five gastric cell lines, and PIK3CA mutations were identified as potentially useful biomarkers for predicting synergy .
Everolimus has demonstrated promising results in phase II clinical trials, but the results were a little disappointing in the GRANITE-1 trial for treating patients with advanced gastric cancer. It is necessary to identify which patients may benefit from mTOR inhibitor therapy in order to improve clinical outcomes. Future studies are needed to establish detailed molecular profiles that can predict sensitivity to mTOR inhibitor therapy. Patient selection based on molecular events known to be associated with mTOR activation, such as the overexpression of PI3K/Akt and various growth factor receptors such as HER2 and insulin-like growth factor receptors, as well as mutations to PI3K and mutations/amplifications of Akt or the downregulation of PTEN, may represent an appropriate way to identify populations that are more likely to demonstrate significant clinical benefits from mTOR inhibitors.
Another way to improve the efficacy of mTOR inhibitors is to combine them with other cytotoxic agents. In mouse models, mTOR inhibitors are able to sensitize cancer cells to chemotherapy. Ongoing clinical studies are currently evaluating everolimus in combination with cytotoxic agents in patients with gastric cancer (Table 1; also, please see http://www.clinicaltrials.gov).
Currently, the NCT01248403 (AIO-STO-0111 RADPAC) trial is evaluating the use of paclitaxel monotherapy (with or without everolimus) for the treatment of progressive advanced gastric cancer after one or two prior chemotherapy regimens. This study is being conducted by the German Arbeitsgemeinschaft Internistische Onkologie with a target enrollment of 480 patients and OS as the primary endpoint. This ongoing trial will evaluate the efficacy of combination mTOR inhibitors with chemotherapy.
In order to more effectively inhibit the mTOR pathway, it is important to better understand the role of mTOR-dependent networks in the progression of gastric cancer. This knowledge will provide the foundation for generating novel strategies that will improve the therapeutic success rate. Second-generation mTOR inhibitors that target both mTORC1 and mTORC2 (TORKinhibs) have demonstrated improved efficacy in early studies and appear to have the potential to circumvent the rapalog resistance that is present in some types of cancers . Future studies that establish the optimal mTOR inhibitor-based drug combinations that target the essential resistance mechanisms are promising and will hopefully translate into direct patient benefits.
This study was supported by National Key Technology R&D Program (2011BAZ03191), and National "Twelfth Five-Year" special science and technology major projects (2011ZX09307-001-05).
Table 1. Ongoing clinical trials evaluating everolimus in combination with cytotoxic agents in patients with gastric cancer.
Key eligibility criteria
Progressive advanced gastric cancer after two prior chemotherapy regimens
Everolimus + capecitabine
Everolimus + cisplatin + 5-FU + leucovorin
Everolimus + paclitaxel + carboplatin
Progressive advanced gastric cancer progressing after one or two prior chemotherapy regimens
Everolimus + paclitaxel vs. paclitaxel + placebo
Abbreviations: BSC, best supportive care; FU, fluorouracil; MTD, maximum tolerated dose; ORR, objective response rate; OS, overall survival.