Accepted Manuscript Title: Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects Author: Omar Abdel-Rahman PII: DOI: Reference:
S1040-8428(14)00100-0 http://dx.doi.org/doi:10.1016/j.critrevonc.2014.05.012 ONCH 1865
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
26-3-2014 16-5-2014 30-5-2014
Please cite this article as: Abdel-Rahman O, Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects, Critical Reviews in Oncology and Hematology (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.05.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Article type: Review article
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Title: Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects
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Authors:
Egypt
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Corresponding author:
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1. Omar Abdel-Rahman: Clinical Oncology department, faculty of medicine, Ain shams university, Cairo,
Dr. Omar Abdel-Rahman, clinical oncology department, faculty of medicine, Ain shams university, Lotfy Elsayed street, Cairo, Egypt. Postal code: 11665
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Fax: 33028656
E mail: [email protected] Short author biography:
Omar Abdel-Rahman: graduated from faculty of medicine, Ain Shams University on December 2005, obtained Master degree in clinical oncology since 2009, he is working currently as an assistant lecturer of clinical oncology, Ain Shams University since 2011
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Title: Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects
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Abstract:
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The prognosis of advanced gastric cancer has been dreadful with the majority of patients dying of their disease within 1 year of the diagnosis. In the advanced stage several therapeutic options can be discussed, including molecular targeted agents,
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but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade bringing
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to several phase II studies; however very few agents moved into phase III clinical trials. The VEGFR-2 inhibitor monoclonal antibody Ramucirumab has been recently approved in advanced progressing gastric cancer. This article reviews the basic science as well as clinical data of VEGF signaling in advanced gastric cancer with special emphasis on the different VEGF
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targeting agents tested previously in this disease.
Key words: Gastric cancer; VEGF; bevacizumab; ramucirumab Page 2 of 35
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Table of contents:
2. Basic biology of VEGF pathway
4. VEGF pathway as a key player in carcinogenesis
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3. The central role of VEGF pathway in angiogenesis
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1. Introduction :
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5. Angiogenesis-oriented subtype classification of gastric cancer 6. Clinical experience with some VEGF pathway -targeted agents Bevacizumab
ii.
Ramucirumab
iii.
VEGFR –targeted Tyrosine kinase inhibitors
iv.
Metronomic chemotherapy
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d
i.
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7. Novel approaches for improving VEGF pathway targeting in gastric cancer- Preclinical evidence i.
RNAi-mediated gene silencing of VEGF gene expression
ii.
The use of standard chemo/biotherapy in combination with novel VEGF-targeted therapeutics for gastric cancer
8. Ongoing projects 9. Conclusions and future directions 10.References:
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1. Introduction :
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Gastric cancer (GC) is the third most common cause of cancer-related deaths worldwide in men and the fifth most common cause of death in women, yielding 738,000 deaths annually. Moreover, gastric cancer is the fourth most common
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malignancy in men, and the fifth most common malignancy in women worldwide, with an estimated 989,600 new cases reported in 2008.(1) There is marked geographic variation with nearly two thirds of all cases occur in developing countries
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in Eastern Europe, South America, and Asia, with 42% of cases in China alone.(2) In the United States, an estimated 21,520 new cases of gastric cancer will be diagnosed in 2011, with an estimated 10,340 deaths due to gastric cancer.(3)
In
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spite of the decline in the incidence of gastric cancers, there has been a relative increase in the incidence of tumors of the
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gastro-esophageal junction (GEJ) and gastric cardia (4). A number of risk factors have been observed for gastric cancer including male gender, Helicobacter pylori infection and smoking. Additionally, a small number of patients may have one of the genetic predisposition syndromes like hereditary
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non-polyposis colorectal cancer or familial adenomatous polyposis among others (5). The prognosis of advanced (unresectable or metastatic) gastric cancer has been dreadful with the majority of patients with advanced GC will die of their disease, most within 1 year of the diagnosis of metastatic disease, thus the search for better treatments for this lethal disease has been a priority for the oncology community (6). In recent years, important signaling pathways leading to tumor proliferation, and worse survival has been discovered with the consequent development of molecular therapies to target these specific oncogenic pathways (7). The most extensively studied pathways include EGFR,
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HER2, VEGF, mTOR and c-MET. In this critical review , We will revise the different preclinical and clinical aspects related to
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the use of VEGF pathway -targeted treatments in this disease with particular focus on the future prospective in that regard.
2. Basic biology of VEGF pathway:
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Vascular endothelial growth factor (VEGF) is one of the most commonly studies molecular markers in health and disease; it was initially identified as an endothelial cell-specific mitogen with demonstrated capacity to induce angiogenesis in
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physiological as well as pathological settings (8.9). Further to this discovery, other members of this family of angiogenic
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growth factors has been identified and this VEGF is now known as VEGFA to be distinguished from other family members including VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Differences between these growth factors were demonstrated in their expression pattern, receptor specificity as well as biological functions (10). Several distinct variants of
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VEGFA have been recognized including (VEGF121, VEGF145, VEGF148, VEGF165, VEGF183, VEGF189 and VEGF206). These variants differ in their receptor specificity and function (11). Downstream signalling of VEGF in tumour cells is mediated by receptor tyrosine kinases (RTKs). These include VEGFR1 (also known as FLT1), VEGFR2 (also known as FLK1 and KDR) and VEGFR3 (also known as FLT4) (12). Most of these receptors are expressed by endothelial cells as well as many tumor types and most interestingly, the expression pattern in tumors correlates with some clinical parameters (13).
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In spite of the fact that some tumor cells lack expression of one or more of the VEGF RTKs but they respond to autocrine and
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paracrine VEGF signals leads us to the search for other types of receptors may contribute to VEGF signaling in these cells. Accordingly, more recently, the neuropilins (NRPs) have generated enormous interest as potential VEGF receptors that may
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contribute to the process of tumor initiation and progression (14,15,16).
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3. The central role of VEGF pathway in angiogenesis:
Angiogenesis is such a complex procedure that it involves multiple alterations as well as mobilization of microenvironment
First, there is loosening of the endothelial cells connections together with nitric oxide production. This leads to
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components. VEGF activation is thought to play a fundamental role in this process through the following biological processes:
increased permeability and vasodilation [17]. Then, VEGF works to induce the expression of multiple proteases includingmatrix metalloproteinases (MMPs) which
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leads to dissolution of the ectracellular matrix around vessels [18]. A third VEGF-mediated biological process has been the recruitment of endothelial progenitor cells and other bone marrow-derived cells to the sites where new blood vessels are forming [19,20]. Accordingly, the development of antiangiogenic strategies for the treatment of cancer as well as other diseases has centered on the VEGF and VEGF signaling pathway.
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4. VEGF pathway as a key player in carcinogenesis:
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To understand the impact of VEGF on carcinogenesis, a number of pathogenetic mechanisms that contribute to increase the level of VEGF have to be clarified. First, Hypoxia works as the principal stimulant of angiogenesis, via the hypoxia-induced
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factor 1/Von Hippel–Lindau protein (HIF-1/pVHL) pathway and in hypoxic environment, HIF-1a evades VHL recognition and thus it becomes free to translocate to the nucleus where it induces the expression of a number of angiogenic growth factors,
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of which VEGF is the most significant [21). Second, in addition to hypoxia, deregulated production of a number of growth factors (PDGF, epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), transforming growth factor a (TGF-a),
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transforming growth factor b (TGF-b), may lead also to an increase in VEGF production. Third, VEGF expression can also be
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induced by mutations leading to continuous intracellular proliferation signals [22]. Regardless of the pathogenetic mechanism leading to increased VEGF, once the production of VEGF exceeds the local antiangiogenic factors, angiogenesis occurs. Importantly, the impact of VEGF has not been shown be only the indirect
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enhancement of the invasive and metastatic potential of cancer cells (i.e., through the increase in neo vessels in the tumor microenvironment) but also a direct mechanism of enhancing the immune evasion of the tumor cells [23, 24]. Accordingly, VEGF over expression (both in serum and tissue ) has been proposed as an adverse prognostic factor in a number of solid tumors including gastric cancer; In order to test this hypothesis, Liu and colleagues conducted a metaanalysis of 44 published studies with 4,794 resected gastric cancer patients to determine the prognostic value of serum and tissue VEGF. The hazard ratio for VEGF subtype for the prediction of overall survival included tissue VEGF (HR=2.13, 95% CI
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1.71-2.65), circulating VEGF (HR=4.22, 95% CI 2.47-7.18), tissue VEGF-C (HR=2.21, 95% CI 1.58-3.09), tissue VEGF-D (HR=1.73,
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95% CI 1.25-2.40). This Meta analysis supports the hypothesis that positive expression of tissue VEGF, circulating VEGF, VEGFC and VEGF-D are all associated with poor prognosis in resected gastric cancer (25).
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In addition to its prognostic value, the predictive value of VEGF was examined in the study of Scartozzi et al., where tumor angiogenesis genotyping was compared against efficacy of first-line platinum-based chemotherapy in metastatic gastric
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cancer patients. In this study, VEGF-A rs25648 maintained an independent role in determining median progression-free survival (hazard ratio: 1.65 95% CI: 1.12-2.78) and overall survival (hazard ratio: 1.58, 95% CI: 1.17-2.65). And thus, it has
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been suggested that VEGF-A rs25648 genotyping may help identify a patient subgroup unlikely to benefit from a first-line,
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platinum-based combination and potential candidates for alternative therapy choices (26).
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5. Angiogenesis-oriented subtype classification of gastric cancer: Gastric cancer is a heterogeneous disease that may be divided into three distinct subtypes – proximal non-diffuse gastric cancer, distal non-diffuse gastric cancer, and diffuse gastric cancer (TABLE-1). These subtypes may be defined based on tumor histology and location, and recently have proven to have a molecular signature as well (27). Epidemiologic evidence supports the above described sub-division, and recently, molecular profiling further supports this emerging concept. An interesting hypothesis to discuss is to examine the clinical relevance of individual subtypes of gastric cancer, and in particular, if anti angiogenic therapies is better utilized with some subtypes over others. Page 8 of 35
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For example, following the results of the subset analysis of the AVAGAST study, in all regions, patients with type 3 gastric
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cancer (GC) had a better prognosis than type 2 GC. In non-Asian patients, bevacizumab therapy appeared to improve outcomes with type 2 and 3 GC (diffuse and distal, non-diffuse gastric cancer) when compared with type 1 GC (proximal, non-
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diffuse gastric cancer). These data suggest that GC subtypes may be important predictors of patient outcome and warrant further prospective evaluation (28).
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Moreover, a comprehensive survey of genomic alterations in gastric cancer by Deng et al. has reported interesting results revealing systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. In this survey,
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copy number alterations were profiled in a panel of 233 gastric cancers and 98 primary matched gastric non-malignant
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samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. This study identifies the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations; including: FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Such an approach may provide an additional support to
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the molecular/angiogenesis subtyping approach of gastric cancer (53).
6. Clinical experience with some VEGF pathway -targeted agents: v.
Bevacizumab:
The most commonly tested agent in this regard is the monoclonal antibody bevacizumab, with a number of phase II and III studies (table-2), The largest study to evaluate bevacizumab in this setting was the AVAGAST study. In this phase 3 study, Page 9 of 35
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774 patients were enrolled; 387 were assigned to each treatment group bevacizumab or placebo followed by cisplatin
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plus capecitabine. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free
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survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo (29). According to the subset
prognosis than type 2 GC. In non-Asian
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study , in all regions, patients with type 3 gastric cancer (GC) had a better
analysis of this
patients, bevacizumab therapy appeared to improve outcomes with type 2 and 3 GC (diffuse and distal, non-diffuse
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gastric cancer) when compared with type 1 GC (proximal, non-diffuse gastric cancer). These data suggest that GC subtypes
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may be important predictors of patient outcome and warrant further prospective evaluation (28). Using in vivo models, immuno histochemistry, and expression analysis, the aim of my proposed research project will be to determine differences in GC subtypes that may predict greater efficacy for antiangiogenic therapies. Similarly, in a smaller phase II study, the efficacy of modified DCF + bevacizumab in 44 patients was examined (30). The
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relationship of gastric cancer subtype and treatment efficacy in this phase II study was explored and interestingly, significant relationships were identified. Specifically, proximal/GEJ gastric cancers (i.e. sub type I) had a remarkable response to treatment with an 85% response rate and a median survival of over 16 months, whereas diffuse gastric cancer had a significantly worse response rate (38%), and median survival of 8.7 months (p = 0.02) (30). Together, these data support the emerging concept that gastric cancer is biologically three individual diseases, and that these diseases are clinically relevant.
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However, the recently reported Chinese AVATAR study did not report such regional/clinico- pathological differences, in
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this phase 3 randomized study 202 adavnced gastric cancer patients were randomized to cisplatin- capecitabine plus either (placebo n = 102 or bevacizumab n = 100) . The primary analysis result did not show a difference in OS for the
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bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95 % CI, 0.79-1.56); P = 0.5567]. Median PFS was also similar in both arms (31).
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Other smaller phase II studies of bevacizumab-based treatments have been published with no report about possible
Ramucirumab:
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vi.
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regional/clinico- pathological differences (table-2)
Ramucirumab is a novel fully human monoclonal antibody against VEGFR2, newly introduced into the armamentarium of systemic treatment for advanced gastric cancer, following the results of the landmark REGARD study , (Ramucirumab
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monotherapy for previously treated advanced gastric or gastro-oesophageal junction cancer). In this study, 355 patients with advanced gastric or gastro-oesophageal junction cancer and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomized to ramucirumab versus placebo. Median overall survival was 5·2 months in patients in the ramucirumab group and 3·8 months in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). However, characteristic antiangiogenic side effects
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were apparent in this study with higher hypertension rates in the ramucirumab group than in the placebo group (38 [16%] vs
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nine [8%]) (34).
Recently, additional data has been released for ramucirumab in advanced gastric cancer at ASCO GI symposium 2014, the
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global RAINBOW study randomized advanced gastric cancer patients to paclitaxel alone or in combination with ramucirumab. The initial results of this study showed that combination arm significantly increased survival compared with paclitaxel alone
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months vs 2.9 months; P < .0001) (35).
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(9.63 months vs 7.36 months, respectively). Additionally, combination therapy arm had better progression-free survival (4.4
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These findings collectively validate VEGFR-2 signalling inhibition as an important therapeutic modality in advanced gastric cancer. And open new prospects in the management of this disease. vii.
VEGFR –targeted Tyrosine kinase inhibitors:
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1. Sunitinib:
Three phase II studies have examined the potential role of sunitinib (both as a single agent and in combination with docetaxel chemotherapy) in the treatment of advanced gastric and gastroesophageal junction cancer. Despite the modest improvement of response rate shown in the three studies, none of them showed statistically significant progression free or overall survival (36,37,38) (table-2).
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2. Sorafenib:
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The combination of sorafenib plus docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction cancer was evaluated in a phase 2 study by the ECOG (ECOG 5203); the study included forty-four
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chemotherapy-naïve patients with advanced gastric and gastroesophageal junction cancer. The results of this study suggest
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that the combination of sorafenib, docetaxel, and cisplatin has an encouraging efficacy profile with tolerable toxicity (39). 3. Cediranib:
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A Japanese phase I study was reported by Satoh et al. evaluating the combination of cediranib in combination with cisplatin
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plus fluoropyrimidine (S-1 or capecitabine) in 14 Japanese patients with previously untreated advanced gastric cancer. They found Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity (40).
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4. Apatinib:
Apatinib is another VEGFR TKI that is undergoing extensive development in multiple solid tumor indications; in a Chinese phase II study, 144 patients with refractory gastric cancer were randomly assigned to receive placebo or apatinib. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017) (23). This suggests the potential utility of this agent in gastric cancer indication and calls for confirmation of the results in a larger phase III randomized study (41).
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Metronomic chemotherapy:
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viii.
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The use of low dose metronomic chemotherapy is one of the most commonly employed antiangiogenic strategies in solid tumors; for gastric cancer, a number of preclinical experiences has suggested the efficacy of this strategy (42,43,44). As a
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consequence, He and coworkers evaluated the impact of Capecitabine "metronomic" chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. They found that metronomic
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fluoropyrimidine-based chemotherapy (45).
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capecitabine is effective and well tolerated as a palliative treatment in elderly patients with advanced gastric cancer after
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7. Novel approaches for improving VEGF pathway targeting in gastric cancer- Preclinical evidence : RNAi-mediated gene silencing of VEGF gene expression:
One suggested novel approach has been the use of RNAi-mediated gene silencing of VEGF gene expression in gastric cancer
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cells; for example, Wang et al. evaluated lentivirus-mediated RNA interfering (RNAi) targeting VEGF-A and/or VEGF-C to silence their expressions in SGC7901 GC cell line. Cell proliferation was measured in vitro; additionally, Suppressive effect on gastric cancer (GC) growth was evaluated in GC bearing mice. They found that lenti-miRNA-VEGF-A+VEGF-C significantly inhibited the cell proliferation and tumor growth, compared with lenti-miRNA-VEGF-A or Lenti-miRNA-VEGF-C (P80%) is located in there is evidence of precursor may
from
well
to
poorly
the gastric cardia which may extend up to glandular dysplasia or in situ differentiated, but the pattern of tumor
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diffuse
range
the gastroesophageal junction and into the carcinoma in the setting of infiltration should not be entirely
May be anywhere in the stomach.
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Type 2: Diffuse
chronic inflammation usually diffuse.
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distal esophagus.
without atrophy The pattern of infiltration is entirely
diffuse
without
excessive extracellular mucin pools (colloid carcinoma is not included).
Type 3: Distal non- The bulk of the tumor is usually located in there is evidence of chronic The dominant pattern is a moderately the distal stomach and may extend up to the gastritis
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diffuse
with
intestinal differentiated
and
intestinal
type
mid body of the stomach or down to the metaplasia and a spectrum of carcinoma without or with minor pylorus.
glandular dysplasia and in situ components of poorly differentiated or carcinoma.
de-differentiated carcinoma.
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Trial
Phase
Number of
1. Bevacizumab studies in advanced gastric cancer: Phase II
Shen et al.(31)
PFS
OS
Grade 3/4 toxicities
65%
8.3 months
12.3 months
Hypertension, gastric perforation and thromboembolic events
bevacizumab, oxaliplatin, and docetaxel
80%
6.6 months
11.1 months
Neutropenia and GI perforation
44 patients
docetaxel, cisplatin, and fluorouracil with bevacizumab
67%
12 months
16.8 months
neutropenia without fever (50%), fatigue (25%), venous thromboembolism (39%)
Phase III
774 (387 assigned to each treatment arm)
bevacizumab or placebo followed by cisplatin plus capecitabine
46.0% v 37.4%
6.7 v 5.3 months
12.1 months vs. 10.1 months
neutropenia (35%, bevacizumab plus fluoropyrimidinecisplatin; 37%, placebo plus fluoropyrimidinecisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%).
Phase III
202 (placebo
capecitabine-
62% vs.
6 months
11.4
Hemorrhage
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Phase II
Phase II
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Ohtsu et al. (29)
ORR
irinotecan, cisplatin, and bevacizumab
38 patients
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El-Rayes et al (33).
Shah et al. (30)
75 patients
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Shah et al (32).
Therapy
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patients
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Table 2: experience with different strategies employed for VEGF targeting in advanced gastric cancer :
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61%
vs. 6.3 months
355 patients ;ramucirumab (n=238) and placebo (n=117)
Ramucirumab or placebo
665 patients
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Phase III
Ramucirumab plus paclitaxel vs. paclitaxel monotherapy
(bevacizumab 4 %, placebo 12 %).
2.8 months vs. 1.7 months
5.2 months vs. 3.8 months
Hypertension, bleeding and thromboembolism
28% vs. 16%
4.4 months vs 2.9 months
9.63 months vs 7.36 months
neutropenia (40.7% vs 18.8%, respectively), leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7% vs 4%),
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Wilke et al. (35)(RAINBOW study)
months vs. 10.5 months
49% vs. 23%
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Phase III
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2. Ramucirumab studies in advanced gastric cancer: Fuchs et al. (34)
cisplatin plus either bevacizumab or placebo
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n = 102; bevacizumab n = 100).
3. Sunitinib in advanced gastric cancer:
Yi et al (36).
Phase II
107 patients
docetaxel and sunitinib vs. docetaxel monotherapy
41.1% vs 14.3%, P=0.002
3.9 months vs. 2.6 months
N/A
HFSR,stomatitis and diarrhea
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Phase II
78 patients
4. Sorafenib in advanced gastric cancer: 44 patients
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Phase II
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Sun et al (39).
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52 patients
Sunitinib monotherapy
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Phase II
Sunitinib monotherapy
3.9%
1.28 months
5.81 months
Anemia and pneumonia
35%
2.3 months
6.8 months
Stomatitis and diarrhea
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Moehler et al (37).
P=0.206
sorafenib in combination with docetaxel and cisplatin
41%
5.8 months
13.6 months
Neutropenia (64% of patients)
5. Metronomic chemotherapy in advanced gastric cancer: Phase II
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He et al. (45)
45 patients
Metronomic capecitabine
51%
3.6 months
7.6 months
diarrhea , stomatitis , and hand-foot syndrome
¥
N/A: not available ; OS: overall survival ; ORR: overall response rate ; PFS: progression free survival
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Type of study
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Cellular Population
Drugs
Endpoints
Results in vitro/in vivo
Lentivirus-mediated RNAi silencing of VEGF genes
the cell proliferation and tumor growth
The Lenti-miRNAVEGF-A+VEGF-C significantly inhibited the cell proliferation and tumor growth
Lentivirus-mediated RNAi silencing of VEGF genes
the cell proliferation and tumor growth
Tumor growth rate and Lymphovascular density were suppressed in vivo
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Study
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Table 3: novel approaches for VEGF targeting in advanced gastric cancer:
SGC7901
Preclinical
Yao et al (47).
Preclinical (xenograft SGC-7901 model)
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Wang et al (46).
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1. The use of RNAi-mediated gene silencing of VEGF gene expression
2. The use of standard chemo/biotherapy in combination with novel VEGF-targeted therapeutics for gastric cancer : Preclinical (xenograft BGC-823 model)
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Wu et al. (49)
Wu et al. (50)
Preclinical (xenograft BGC-823 model)
capecitabine alone and combined with the angiogenic inhibitor (-)epigallocatechin-3gallate (EGCG)
tumor growth, side effects and the number of days of survival of mice
metronomic capecitabine inhibited angiogenesis, growth of gastric cancer and improved survival with less toxicity, and the effects were further enhanced by the concurrent administration of EGCG
Low dose docetaxel alone and combined with the angiogenic inhibitor (-)-
tumor growth, side effects and the number of days of survival of mice
metronomic docetaxel inhibited angiogenesis, growth of gastric cancer and improved
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Singh et al (52).
Preclinical (xenograft NCI-N87 model)
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survival with less toxicity, and the effects were further enhanced by the concurrent administration of EGCG
everolimus in combination with metronomic cyclophosphamide
tumor growth, side effects and the number of days of survival of mice
The combination of everolimus and cyclophosphamide resulted in a striking and highly significant long-term tumor growth control
Trastuzumab plus VEGF-Trap binding to VEGF-A
the cell proliferation and tumor growth
The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGFTrap alone
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Preclinical (xenograft NCI-N87 model)
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Cejka et al.(51)
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epigallocatechin-3gallate (EGCG)
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Table 4: list of ongoing studies for VEGF targeting agents in advanced gastric cancer: Title of the Study Clinicaltrials.gov Study locations Phase Therapy identifier
Estimated completion date
FLO (5FU, leucovorin and oxaliplatin )+/Pazopanib
Recruiting
May 2015
Phase II
FOLFOX +/- ZivAflibercept
Recruiting
February 2015
Roswell Park Cancer Institute
Phase I
FOLFIRI + sunitinib
This study is ongoing, but not recruiting participants
December 2014
8 Japanese centers
Phase II
Dovitinib
This study has been September 2013 completed but full text results are not yet available
Charite University, Berlin, Germany
FOLFOX +/- ZivAflibercept for Esophageal and Gastric Cancer
NCT01747551
Dana-Farber Cancer Institute
Sunitinib, Irinotecan, Fluorouracil, and Leucovorin In Treating Patients With Advanced Stomach Cancer or Gastroesophageal Cancer
NCT00524186
Phase II
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NCT01503372
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FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer
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Status
A Phase II Study to NCT01576380 Evaluate Efficacy and Safety of Dovitinib (TKI258)
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Ramucirumab
Recruiting
July 2015
FOLFOX +Ramucirumab
This study is ongoing, but not recruiting participants
May 2014
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Phase II
58 centers in the US
Phase II
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A Study of Ramucirumab in Patients With Gastric, Esophageal and Gastroesophageal Cancer
11 centers in Japan
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A Study of NCT01983878 Ramucirumab in Treating Japanese Participants With Metastatic Gastric or Gastroesophageal Junction Cancer
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in Advanced Scirrhous Gastric Carcinoma Patients
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Highlights:
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Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide.
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Many VEGF-targeted agents were clinically tested in GC and they showed modest activity with considerable toxicity.
Preclinical as well as clinical ramucirumab data in GC provide a new hope in that direction.
Ac
ce pt
further clinical evaluation.
ed
The use of biomarkers to select GC patients for VEGF- targeted therapy should be considered for
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S1040-8428(14)00100-0 http://dx.doi.org/doi:10.1016/j.critrevonc.2014.05.012 ONCH 1865
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
26-3-2014 16-5-2014 30-5-2014
Please cite this article as: Abdel-Rahman O, Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects, Critical Reviews in Oncology and Hematology (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.05.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Article type: Review article
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Title: Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects
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Authors:
Egypt
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Corresponding author:
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1. Omar Abdel-Rahman: Clinical Oncology department, faculty of medicine, Ain shams university, Cairo,
Dr. Omar Abdel-Rahman, clinical oncology department, faculty of medicine, Ain shams university, Lotfy Elsayed street, Cairo, Egypt. Postal code: 11665
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Fax: 33028656
E mail: [email protected] Short author biography:
Omar Abdel-Rahman: graduated from faculty of medicine, Ain Shams University on December 2005, obtained Master degree in clinical oncology since 2009, he is working currently as an assistant lecturer of clinical oncology, Ain Shams University since 2011
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Title: Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer; preclinical and clinical aspects
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Abstract:
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The prognosis of advanced gastric cancer has been dreadful with the majority of patients dying of their disease within 1 year of the diagnosis. In the advanced stage several therapeutic options can be discussed, including molecular targeted agents,
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but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade bringing
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to several phase II studies; however very few agents moved into phase III clinical trials. The VEGFR-2 inhibitor monoclonal antibody Ramucirumab has been recently approved in advanced progressing gastric cancer. This article reviews the basic science as well as clinical data of VEGF signaling in advanced gastric cancer with special emphasis on the different VEGF
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targeting agents tested previously in this disease.
Key words: Gastric cancer; VEGF; bevacizumab; ramucirumab Page 2 of 35
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Table of contents:
2. Basic biology of VEGF pathway
4. VEGF pathway as a key player in carcinogenesis
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3. The central role of VEGF pathway in angiogenesis
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1. Introduction :
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5. Angiogenesis-oriented subtype classification of gastric cancer 6. Clinical experience with some VEGF pathway -targeted agents Bevacizumab
ii.
Ramucirumab
iii.
VEGFR –targeted Tyrosine kinase inhibitors
iv.
Metronomic chemotherapy
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i.
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7. Novel approaches for improving VEGF pathway targeting in gastric cancer- Preclinical evidence i.
RNAi-mediated gene silencing of VEGF gene expression
ii.
The use of standard chemo/biotherapy in combination with novel VEGF-targeted therapeutics for gastric cancer
8. Ongoing projects 9. Conclusions and future directions 10.References:
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1. Introduction :
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Gastric cancer (GC) is the third most common cause of cancer-related deaths worldwide in men and the fifth most common cause of death in women, yielding 738,000 deaths annually. Moreover, gastric cancer is the fourth most common
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malignancy in men, and the fifth most common malignancy in women worldwide, with an estimated 989,600 new cases reported in 2008.(1) There is marked geographic variation with nearly two thirds of all cases occur in developing countries
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in Eastern Europe, South America, and Asia, with 42% of cases in China alone.(2) In the United States, an estimated 21,520 new cases of gastric cancer will be diagnosed in 2011, with an estimated 10,340 deaths due to gastric cancer.(3)
In
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spite of the decline in the incidence of gastric cancers, there has been a relative increase in the incidence of tumors of the
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gastro-esophageal junction (GEJ) and gastric cardia (4). A number of risk factors have been observed for gastric cancer including male gender, Helicobacter pylori infection and smoking. Additionally, a small number of patients may have one of the genetic predisposition syndromes like hereditary
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non-polyposis colorectal cancer or familial adenomatous polyposis among others (5). The prognosis of advanced (unresectable or metastatic) gastric cancer has been dreadful with the majority of patients with advanced GC will die of their disease, most within 1 year of the diagnosis of metastatic disease, thus the search for better treatments for this lethal disease has been a priority for the oncology community (6). In recent years, important signaling pathways leading to tumor proliferation, and worse survival has been discovered with the consequent development of molecular therapies to target these specific oncogenic pathways (7). The most extensively studied pathways include EGFR,
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HER2, VEGF, mTOR and c-MET. In this critical review , We will revise the different preclinical and clinical aspects related to
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the use of VEGF pathway -targeted treatments in this disease with particular focus on the future prospective in that regard.
2. Basic biology of VEGF pathway:
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Vascular endothelial growth factor (VEGF) is one of the most commonly studies molecular markers in health and disease; it was initially identified as an endothelial cell-specific mitogen with demonstrated capacity to induce angiogenesis in
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physiological as well as pathological settings (8.9). Further to this discovery, other members of this family of angiogenic
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growth factors has been identified and this VEGF is now known as VEGFA to be distinguished from other family members including VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Differences between these growth factors were demonstrated in their expression pattern, receptor specificity as well as biological functions (10). Several distinct variants of
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VEGFA have been recognized including (VEGF121, VEGF145, VEGF148, VEGF165, VEGF183, VEGF189 and VEGF206). These variants differ in their receptor specificity and function (11). Downstream signalling of VEGF in tumour cells is mediated by receptor tyrosine kinases (RTKs). These include VEGFR1 (also known as FLT1), VEGFR2 (also known as FLK1 and KDR) and VEGFR3 (also known as FLT4) (12). Most of these receptors are expressed by endothelial cells as well as many tumor types and most interestingly, the expression pattern in tumors correlates with some clinical parameters (13).
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In spite of the fact that some tumor cells lack expression of one or more of the VEGF RTKs but they respond to autocrine and
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paracrine VEGF signals leads us to the search for other types of receptors may contribute to VEGF signaling in these cells. Accordingly, more recently, the neuropilins (NRPs) have generated enormous interest as potential VEGF receptors that may
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contribute to the process of tumor initiation and progression (14,15,16).
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3. The central role of VEGF pathway in angiogenesis:
Angiogenesis is such a complex procedure that it involves multiple alterations as well as mobilization of microenvironment
First, there is loosening of the endothelial cells connections together with nitric oxide production. This leads to
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components. VEGF activation is thought to play a fundamental role in this process through the following biological processes:
increased permeability and vasodilation [17]. Then, VEGF works to induce the expression of multiple proteases includingmatrix metalloproteinases (MMPs) which
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leads to dissolution of the ectracellular matrix around vessels [18]. A third VEGF-mediated biological process has been the recruitment of endothelial progenitor cells and other bone marrow-derived cells to the sites where new blood vessels are forming [19,20]. Accordingly, the development of antiangiogenic strategies for the treatment of cancer as well as other diseases has centered on the VEGF and VEGF signaling pathway.
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4. VEGF pathway as a key player in carcinogenesis:
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To understand the impact of VEGF on carcinogenesis, a number of pathogenetic mechanisms that contribute to increase the level of VEGF have to be clarified. First, Hypoxia works as the principal stimulant of angiogenesis, via the hypoxia-induced
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factor 1/Von Hippel–Lindau protein (HIF-1/pVHL) pathway and in hypoxic environment, HIF-1a evades VHL recognition and thus it becomes free to translocate to the nucleus where it induces the expression of a number of angiogenic growth factors,
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of which VEGF is the most significant [21). Second, in addition to hypoxia, deregulated production of a number of growth factors (PDGF, epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), transforming growth factor a (TGF-a),
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transforming growth factor b (TGF-b), may lead also to an increase in VEGF production. Third, VEGF expression can also be
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induced by mutations leading to continuous intracellular proliferation signals [22]. Regardless of the pathogenetic mechanism leading to increased VEGF, once the production of VEGF exceeds the local antiangiogenic factors, angiogenesis occurs. Importantly, the impact of VEGF has not been shown be only the indirect
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enhancement of the invasive and metastatic potential of cancer cells (i.e., through the increase in neo vessels in the tumor microenvironment) but also a direct mechanism of enhancing the immune evasion of the tumor cells [23, 24]. Accordingly, VEGF over expression (both in serum and tissue ) has been proposed as an adverse prognostic factor in a number of solid tumors including gastric cancer; In order to test this hypothesis, Liu and colleagues conducted a metaanalysis of 44 published studies with 4,794 resected gastric cancer patients to determine the prognostic value of serum and tissue VEGF. The hazard ratio for VEGF subtype for the prediction of overall survival included tissue VEGF (HR=2.13, 95% CI
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1.71-2.65), circulating VEGF (HR=4.22, 95% CI 2.47-7.18), tissue VEGF-C (HR=2.21, 95% CI 1.58-3.09), tissue VEGF-D (HR=1.73,
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95% CI 1.25-2.40). This Meta analysis supports the hypothesis that positive expression of tissue VEGF, circulating VEGF, VEGFC and VEGF-D are all associated with poor prognosis in resected gastric cancer (25).
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In addition to its prognostic value, the predictive value of VEGF was examined in the study of Scartozzi et al., where tumor angiogenesis genotyping was compared against efficacy of first-line platinum-based chemotherapy in metastatic gastric
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cancer patients. In this study, VEGF-A rs25648 maintained an independent role in determining median progression-free survival (hazard ratio: 1.65 95% CI: 1.12-2.78) and overall survival (hazard ratio: 1.58, 95% CI: 1.17-2.65). And thus, it has
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been suggested that VEGF-A rs25648 genotyping may help identify a patient subgroup unlikely to benefit from a first-line,
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platinum-based combination and potential candidates for alternative therapy choices (26).
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5. Angiogenesis-oriented subtype classification of gastric cancer: Gastric cancer is a heterogeneous disease that may be divided into three distinct subtypes – proximal non-diffuse gastric cancer, distal non-diffuse gastric cancer, and diffuse gastric cancer (TABLE-1). These subtypes may be defined based on tumor histology and location, and recently have proven to have a molecular signature as well (27). Epidemiologic evidence supports the above described sub-division, and recently, molecular profiling further supports this emerging concept. An interesting hypothesis to discuss is to examine the clinical relevance of individual subtypes of gastric cancer, and in particular, if anti angiogenic therapies is better utilized with some subtypes over others. Page 8 of 35
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For example, following the results of the subset analysis of the AVAGAST study, in all regions, patients with type 3 gastric
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cancer (GC) had a better prognosis than type 2 GC. In non-Asian patients, bevacizumab therapy appeared to improve outcomes with type 2 and 3 GC (diffuse and distal, non-diffuse gastric cancer) when compared with type 1 GC (proximal, non-
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diffuse gastric cancer). These data suggest that GC subtypes may be important predictors of patient outcome and warrant further prospective evaluation (28).
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Moreover, a comprehensive survey of genomic alterations in gastric cancer by Deng et al. has reported interesting results revealing systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. In this survey,
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copy number alterations were profiled in a panel of 233 gastric cancers and 98 primary matched gastric non-malignant
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samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. This study identifies the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations; including: FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Such an approach may provide an additional support to
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the molecular/angiogenesis subtyping approach of gastric cancer (53).
6. Clinical experience with some VEGF pathway -targeted agents: v.
Bevacizumab:
The most commonly tested agent in this regard is the monoclonal antibody bevacizumab, with a number of phase II and III studies (table-2), The largest study to evaluate bevacizumab in this setting was the AVAGAST study. In this phase 3 study, Page 9 of 35
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774 patients were enrolled; 387 were assigned to each treatment group bevacizumab or placebo followed by cisplatin
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plus capecitabine. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free
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survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo (29). According to the subset
prognosis than type 2 GC. In non-Asian
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study , in all regions, patients with type 3 gastric cancer (GC) had a better
analysis of this
patients, bevacizumab therapy appeared to improve outcomes with type 2 and 3 GC (diffuse and distal, non-diffuse
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gastric cancer) when compared with type 1 GC (proximal, non-diffuse gastric cancer). These data suggest that GC subtypes
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may be important predictors of patient outcome and warrant further prospective evaluation (28). Using in vivo models, immuno histochemistry, and expression analysis, the aim of my proposed research project will be to determine differences in GC subtypes that may predict greater efficacy for antiangiogenic therapies. Similarly, in a smaller phase II study, the efficacy of modified DCF + bevacizumab in 44 patients was examined (30). The
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relationship of gastric cancer subtype and treatment efficacy in this phase II study was explored and interestingly, significant relationships were identified. Specifically, proximal/GEJ gastric cancers (i.e. sub type I) had a remarkable response to treatment with an 85% response rate and a median survival of over 16 months, whereas diffuse gastric cancer had a significantly worse response rate (38%), and median survival of 8.7 months (p = 0.02) (30). Together, these data support the emerging concept that gastric cancer is biologically three individual diseases, and that these diseases are clinically relevant.
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However, the recently reported Chinese AVATAR study did not report such regional/clinico- pathological differences, in
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this phase 3 randomized study 202 adavnced gastric cancer patients were randomized to cisplatin- capecitabine plus either (placebo n = 102 or bevacizumab n = 100) . The primary analysis result did not show a difference in OS for the
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bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95 % CI, 0.79-1.56); P = 0.5567]. Median PFS was also similar in both arms (31).
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Other smaller phase II studies of bevacizumab-based treatments have been published with no report about possible
Ramucirumab:
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vi.
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regional/clinico- pathological differences (table-2)
Ramucirumab is a novel fully human monoclonal antibody against VEGFR2, newly introduced into the armamentarium of systemic treatment for advanced gastric cancer, following the results of the landmark REGARD study , (Ramucirumab
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monotherapy for previously treated advanced gastric or gastro-oesophageal junction cancer). In this study, 355 patients with advanced gastric or gastro-oesophageal junction cancer and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomized to ramucirumab versus placebo. Median overall survival was 5·2 months in patients in the ramucirumab group and 3·8 months in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). However, characteristic antiangiogenic side effects
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were apparent in this study with higher hypertension rates in the ramucirumab group than in the placebo group (38 [16%] vs
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nine [8%]) (34).
Recently, additional data has been released for ramucirumab in advanced gastric cancer at ASCO GI symposium 2014, the
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global RAINBOW study randomized advanced gastric cancer patients to paclitaxel alone or in combination with ramucirumab. The initial results of this study showed that combination arm significantly increased survival compared with paclitaxel alone
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months vs 2.9 months; P < .0001) (35).
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(9.63 months vs 7.36 months, respectively). Additionally, combination therapy arm had better progression-free survival (4.4
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These findings collectively validate VEGFR-2 signalling inhibition as an important therapeutic modality in advanced gastric cancer. And open new prospects in the management of this disease. vii.
VEGFR –targeted Tyrosine kinase inhibitors:
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1. Sunitinib:
Three phase II studies have examined the potential role of sunitinib (both as a single agent and in combination with docetaxel chemotherapy) in the treatment of advanced gastric and gastroesophageal junction cancer. Despite the modest improvement of response rate shown in the three studies, none of them showed statistically significant progression free or overall survival (36,37,38) (table-2).
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2. Sorafenib:
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The combination of sorafenib plus docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction cancer was evaluated in a phase 2 study by the ECOG (ECOG 5203); the study included forty-four
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chemotherapy-naïve patients with advanced gastric and gastroesophageal junction cancer. The results of this study suggest
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that the combination of sorafenib, docetaxel, and cisplatin has an encouraging efficacy profile with tolerable toxicity (39). 3. Cediranib:
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A Japanese phase I study was reported by Satoh et al. evaluating the combination of cediranib in combination with cisplatin
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plus fluoropyrimidine (S-1 or capecitabine) in 14 Japanese patients with previously untreated advanced gastric cancer. They found Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity (40).
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4. Apatinib:
Apatinib is another VEGFR TKI that is undergoing extensive development in multiple solid tumor indications; in a Chinese phase II study, 144 patients with refractory gastric cancer were randomly assigned to receive placebo or apatinib. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017) (23). This suggests the potential utility of this agent in gastric cancer indication and calls for confirmation of the results in a larger phase III randomized study (41).
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Metronomic chemotherapy:
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viii.
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The use of low dose metronomic chemotherapy is one of the most commonly employed antiangiogenic strategies in solid tumors; for gastric cancer, a number of preclinical experiences has suggested the efficacy of this strategy (42,43,44). As a
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consequence, He and coworkers evaluated the impact of Capecitabine "metronomic" chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. They found that metronomic
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fluoropyrimidine-based chemotherapy (45).
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capecitabine is effective and well tolerated as a palliative treatment in elderly patients with advanced gastric cancer after
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7. Novel approaches for improving VEGF pathway targeting in gastric cancer- Preclinical evidence : RNAi-mediated gene silencing of VEGF gene expression:
One suggested novel approach has been the use of RNAi-mediated gene silencing of VEGF gene expression in gastric cancer
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cells; for example, Wang et al. evaluated lentivirus-mediated RNA interfering (RNAi) targeting VEGF-A and/or VEGF-C to silence their expressions in SGC7901 GC cell line. Cell proliferation was measured in vitro; additionally, Suppressive effect on gastric cancer (GC) growth was evaluated in GC bearing mice. They found that lenti-miRNA-VEGF-A+VEGF-C significantly inhibited the cell proliferation and tumor growth, compared with lenti-miRNA-VEGF-A or Lenti-miRNA-VEGF-C (P80%) is located in there is evidence of precursor may
from
well
to
poorly
the gastric cardia which may extend up to glandular dysplasia or in situ differentiated, but the pattern of tumor
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diffuse
range
the gastroesophageal junction and into the carcinoma in the setting of infiltration should not be entirely
May be anywhere in the stomach.
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Type 2: Diffuse
chronic inflammation usually diffuse.
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distal esophagus.
without atrophy The pattern of infiltration is entirely
diffuse
without
excessive extracellular mucin pools (colloid carcinoma is not included).
Type 3: Distal non- The bulk of the tumor is usually located in there is evidence of chronic The dominant pattern is a moderately the distal stomach and may extend up to the gastritis
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diffuse
with
intestinal differentiated
and
intestinal
type
mid body of the stomach or down to the metaplasia and a spectrum of carcinoma without or with minor pylorus.
glandular dysplasia and in situ components of poorly differentiated or carcinoma.
de-differentiated carcinoma.
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Trial
Phase
Number of
1. Bevacizumab studies in advanced gastric cancer: Phase II
Shen et al.(31)
PFS
OS
Grade 3/4 toxicities
65%
8.3 months
12.3 months
Hypertension, gastric perforation and thromboembolic events
bevacizumab, oxaliplatin, and docetaxel
80%
6.6 months
11.1 months
Neutropenia and GI perforation
44 patients
docetaxel, cisplatin, and fluorouracil with bevacizumab
67%
12 months
16.8 months
neutropenia without fever (50%), fatigue (25%), venous thromboembolism (39%)
Phase III
774 (387 assigned to each treatment arm)
bevacizumab or placebo followed by cisplatin plus capecitabine
46.0% v 37.4%
6.7 v 5.3 months
12.1 months vs. 10.1 months
neutropenia (35%, bevacizumab plus fluoropyrimidinecisplatin; 37%, placebo plus fluoropyrimidinecisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%).
Phase III
202 (placebo
capecitabine-
62% vs.
6 months
11.4
Hemorrhage
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Phase II
Phase II
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Ohtsu et al. (29)
ORR
irinotecan, cisplatin, and bevacizumab
38 patients
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El-Rayes et al (33).
Shah et al. (30)
75 patients
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Shah et al (32).
Therapy
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patients
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Table 2: experience with different strategies employed for VEGF targeting in advanced gastric cancer :
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61%
vs. 6.3 months
355 patients ;ramucirumab (n=238) and placebo (n=117)
Ramucirumab or placebo
665 patients
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Phase III
Ramucirumab plus paclitaxel vs. paclitaxel monotherapy
(bevacizumab 4 %, placebo 12 %).
2.8 months vs. 1.7 months
5.2 months vs. 3.8 months
Hypertension, bleeding and thromboembolism
28% vs. 16%
4.4 months vs 2.9 months
9.63 months vs 7.36 months
neutropenia (40.7% vs 18.8%, respectively), leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7% vs 4%),
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Wilke et al. (35)(RAINBOW study)
months vs. 10.5 months
49% vs. 23%
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Phase III
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2. Ramucirumab studies in advanced gastric cancer: Fuchs et al. (34)
cisplatin plus either bevacizumab or placebo
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n = 102; bevacizumab n = 100).
3. Sunitinib in advanced gastric cancer:
Yi et al (36).
Phase II
107 patients
docetaxel and sunitinib vs. docetaxel monotherapy
41.1% vs 14.3%, P=0.002
3.9 months vs. 2.6 months
N/A
HFSR,stomatitis and diarrhea
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Phase II
78 patients
4. Sorafenib in advanced gastric cancer: 44 patients
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Phase II
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Sun et al (39).
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52 patients
Sunitinib monotherapy
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Phase II
Sunitinib monotherapy
3.9%
1.28 months
5.81 months
Anemia and pneumonia
35%
2.3 months
6.8 months
Stomatitis and diarrhea
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Moehler et al (37).
P=0.206
sorafenib in combination with docetaxel and cisplatin
41%
5.8 months
13.6 months
Neutropenia (64% of patients)
5. Metronomic chemotherapy in advanced gastric cancer: Phase II
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He et al. (45)
45 patients
Metronomic capecitabine
51%
3.6 months
7.6 months
diarrhea , stomatitis , and hand-foot syndrome
¥
N/A: not available ; OS: overall survival ; ORR: overall response rate ; PFS: progression free survival
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Type of study
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Cellular Population
Drugs
Endpoints
Results in vitro/in vivo
Lentivirus-mediated RNAi silencing of VEGF genes
the cell proliferation and tumor growth
The Lenti-miRNAVEGF-A+VEGF-C significantly inhibited the cell proliferation and tumor growth
Lentivirus-mediated RNAi silencing of VEGF genes
the cell proliferation and tumor growth
Tumor growth rate and Lymphovascular density were suppressed in vivo
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Study
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Table 3: novel approaches for VEGF targeting in advanced gastric cancer:
SGC7901
Preclinical
Yao et al (47).
Preclinical (xenograft SGC-7901 model)
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Wang et al (46).
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1. The use of RNAi-mediated gene silencing of VEGF gene expression
2. The use of standard chemo/biotherapy in combination with novel VEGF-targeted therapeutics for gastric cancer : Preclinical (xenograft BGC-823 model)
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Wu et al. (49)
Wu et al. (50)
Preclinical (xenograft BGC-823 model)
capecitabine alone and combined with the angiogenic inhibitor (-)epigallocatechin-3gallate (EGCG)
tumor growth, side effects and the number of days of survival of mice
metronomic capecitabine inhibited angiogenesis, growth of gastric cancer and improved survival with less toxicity, and the effects were further enhanced by the concurrent administration of EGCG
Low dose docetaxel alone and combined with the angiogenic inhibitor (-)-
tumor growth, side effects and the number of days of survival of mice
metronomic docetaxel inhibited angiogenesis, growth of gastric cancer and improved
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Singh et al (52).
Preclinical (xenograft NCI-N87 model)
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survival with less toxicity, and the effects were further enhanced by the concurrent administration of EGCG
everolimus in combination with metronomic cyclophosphamide
tumor growth, side effects and the number of days of survival of mice
The combination of everolimus and cyclophosphamide resulted in a striking and highly significant long-term tumor growth control
Trastuzumab plus VEGF-Trap binding to VEGF-A
the cell proliferation and tumor growth
The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGFTrap alone
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Preclinical (xenograft NCI-N87 model)
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Cejka et al.(51)
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epigallocatechin-3gallate (EGCG)
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Table 4: list of ongoing studies for VEGF targeting agents in advanced gastric cancer: Title of the Study Clinicaltrials.gov Study locations Phase Therapy identifier
Estimated completion date
FLO (5FU, leucovorin and oxaliplatin )+/Pazopanib
Recruiting
May 2015
Phase II
FOLFOX +/- ZivAflibercept
Recruiting
February 2015
Roswell Park Cancer Institute
Phase I
FOLFIRI + sunitinib
This study is ongoing, but not recruiting participants
December 2014
8 Japanese centers
Phase II
Dovitinib
This study has been September 2013 completed but full text results are not yet available
Charite University, Berlin, Germany
FOLFOX +/- ZivAflibercept for Esophageal and Gastric Cancer
NCT01747551
Dana-Farber Cancer Institute
Sunitinib, Irinotecan, Fluorouracil, and Leucovorin In Treating Patients With Advanced Stomach Cancer or Gastroesophageal Cancer
NCT00524186
Phase II
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NCT01503372
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FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer
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Status
A Phase II Study to NCT01576380 Evaluate Efficacy and Safety of Dovitinib (TKI258)
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Ramucirumab
Recruiting
July 2015
FOLFOX +Ramucirumab
This study is ongoing, but not recruiting participants
May 2014
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Phase II
58 centers in the US
Phase II
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A Study of Ramucirumab in Patients With Gastric, Esophageal and Gastroesophageal Cancer
11 centers in Japan
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A Study of NCT01983878 Ramucirumab in Treating Japanese Participants With Metastatic Gastric or Gastroesophageal Junction Cancer
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in Advanced Scirrhous Gastric Carcinoma Patients
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Highlights:
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Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide.
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Many VEGF-targeted agents were clinically tested in GC and they showed modest activity with considerable toxicity.
Preclinical as well as clinical ramucirumab data in GC provide a new hope in that direction.
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ce pt
further clinical evaluation.
ed
The use of biomarkers to select GC patients for VEGF- targeted therapy should be considered for
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