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signaling is regulated by MEK1 and MEK2, which are differ substantially in their underlying etiology and
responsible for phosphorylating and activating the fi nal tumorigenesis. A tri-modal treatment strategy consisting
downstream signaling molecules ERK1 and 2. ERK1/2 of radiotherapy, chemotherapy and surgery is standard
[23]
regulates cellular activity by acting on more than 100 for patients with local and/or advanced cancer of the
substrates, both in the cytoplasm and nucleus. Ras also esophagus. [42,43] Unfortunately, as the 5-year survival rate
regulates the PI3K/AKT/mTOR, the phospholipase remains < 15% the majority of patients at advanced stages
[44]
C/protein kinase C, and the Ral guanine nucleotide of the disease fails to benefi t from these treatments,
dissociation stimulator pathways. [26,27] and more effective therapies are eagerly awaited.
Therefore, clinical trials of targeted drugs as monotherapy
Wnt pathway
or in combination with conventional chemotherapy have
Extensive descriptions of the roles of Wnt signaling been recently conducted for patients with esophageal
in development and disease can be found in recent cancer. However, a recent randomized Phase III trial
reviews. [28,29] The canonical Wnt/β-catenin signaling demonstrated that the addition of cetuximab, a humanized
pathway involves the sequestration of β-catenin from mouse EGFR mAb, to capecitabine-cisplatin provided
a destruction complex, which consists of adenomatous no additional benefi t to chemotherapy alone in the
polyposis coli glycogen synthase kinase 3-α, casein fi rst-line treatment of advanced esophagogastric AC.
[45]
kinase 1 and axin. The activation of Wnt/β-catenin Similarly, the addition of panitumumab; another EGFR
signaling is important for both the initiation and mAb to epirubicin; oxaliplatin and capecitabine did not
[30]
progression of cancers in various tissues. Therefore, increase overall survival (OS) of patients with advanced
the disruption of Wnt/β-catenin signaling represents an esophagogastric AC. However, nimotuzumab, a
[46]
opportunity for rational cancer chemoprevention and humanized EGFR mAb, in combination with standard
[30]
therapy. In CRC, 90% of all tumors have a mutation chemotherapy (cisplatin plus 5-fl uorouracil [5-FU]), has
in a key regulatory factor of the Wnt/β-catenin signaling shown a good therapeutic response in a pilot study of
pathway that results in pathway activation, and up to 80% patients with ESCC. [47]
of tumors exhibit nuclear accumulation of β-catenin. [31-33]
VEGF is up-regulated in EAC, and overexpression
Nuclear factor-κB pathway of VEGF protein has been reported as a negative
[9]
prognostic marker in ESCC. Therefore, VEGF may
In recent years, several studies have revealed the be a potential therapeutic target in esophageal cancers.
connection between infl ammation and carcinogenesis. [34,35] Although Phase II trials demonstrated that the addition
In chronic infl ammation, cytokines and chemokines of bevacizumab to conventional chemotherapy improved
produced by infl ammatory cells propagate a localized response rates (RRs) in patients with esophagogastric
infl ammatory response and enhance the survival AC, no Phase III trial has demonstrated a survival
[48]
of pre-malignant cells by activating the nuclear benefi t of bevacizumab. [49]
factor-κB (NF-κB) pathway. NF-κB is aberrantly
activated in 50% of CRC patients and those with The effi cacy of molecular targeted drugs for esophageal
colitis-associated tumors, and mouse studies have cancer is still controversial. Further investigations to
established that NF-κB plays a role in the development elucidate molecular mechanisms of esophageal cancer are
of colitis-associated cancer. [36,37] As the NF-κB pathway needed to establish effective targeted treatment strategies.
plays a pivotal role in apoptosis, tumor promotion Gastric cancer
and maintenance, inhibitors of this signaling pathway
would be useful in CRC therapy. Non-steroidal GC is the fourth most commonly diagnosed cancer
anti-infl ammatory drugs (NSAIDs) exhibit anti-neoplastic and the second leading cause of cancer mortality
[50]
[38]
activities in the colon. Stimulation of NF-κB worldwide. Despite the recent progress in cancer
expression is inhibited by various NSAIDs, indicating treatment, the prognosis of patients with advanced
that NSAIDs may act as chemopreventive agents. Several GC remains poor. The understanding of molecular
studies, including randomized trials, have shown that pathways involved in gastric carcinogenesis offers novel
regular use of NSAIDs is associated with decreased CRC treatment options. When compared with chemotherapy
incidence and mortality. [39,40] alone, the HER-2-targeting antibody trastuzumabin
combination with capecitabine/cisplatin was shown to
Clinical Application of Targeted Drugs improve the survival of advanced GC patients harboring
HER-2 overexpression caused by gene amplifi cation.
[51]
Esophageal cancer
Another agent with promising results in clinical trials
Esophageal cancer is the eighth most frequent cause is ramucirumab, an antibody targeting VEGFR-2. [52,53]
of cancer death and is increasing worldwide. This However, clinical trials have failed to demonstrate
[41]
malignancy comprises two major histologic types, the benefi t of agents targeting EGFR (cetuximab,
esophageal squamous cell carcinoma (ESCC) and panitumumab), [45,46] VEGF-A (bevacizumab) or
[54]
esophageal adenocarcinoma (EAC). ESCC and EAC mTOR (everolimus). The results of Phase III trials to
[55]
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 165