Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
* Correspondence to: Dr J. Tabernero, Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119129, 08035, Barcelona, Spain. Tel: +34-93-274-6085; Fax: +34-93-274-6059; E-mail: jtabernero{at}vhebron.net
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Abstract |
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Key words: targeted therapies, EGFR inhibitors, angiogenesis inhibitors, gastric cancer, esophageal cancer
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Introduction |
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For the purpose of this review, these novel agents will be divided into five different categories according to the pattern of acquired capabilities of the malignant cells, elegantly described by Hanahan and Weinberg [11]: (1) agents directed to interfere with the self-sufficiency in growth signals, such as epidermal growth factor receptor (EGFR) inhibitors; (2) agents directed to inhibit the angiogenesis process; (3) agents directed to interfere with the limitless replicative potential, such as cell cycle inhibitors; (4) agents directed to promote apoptosis, such as proteasome inhibitors; and (5) agents directed to inhibit the tissue invasion and the metastasis processes, such as matrix metalloproteinases inhibitors.
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Epidermal growth factor receptor inhibitors |
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The area of research continues to expand and a number of issues are of particular interest for the future development of EGFR inhibitors in GC and EC. First, it is not known what level of EGFR expression is required to obtain clinical benefit. While a relationship appears to exist between the levels of the erbB-2 receptor and response to trastuzumab (Herceptin®), no clear association has emerged between the levels of EGFR and response to EGFR inhibitors. Secondly, it remains to be established which patients will show the greatest response to these therapies. There is a clear need to identify predictor factors of response (e.g. gene and proteomic profile) in order to select the patients who have a fair chance of responding to EGFR inhibitors. Several studies in patients with advanced CRC treated with anti-EGFR mAbs have incorporated transcriptional profiling end points and the preliminary results have been presented [30]. In patients with advanced non-small-cell lung cancer (NSCLC), the presence of mutations in the tyrosine kinase domain of the EGFR has been shown to play an instrumental role in the clinical activity of the TKIs, gefitinib and erlotinib [31
33
]. By contrast, patients with advanced CRC rarely show mutations in the catalytic domain of the EGFR and no correlation has been observed between these mutations and clinical activity in this population [34
]. To date, there is no information on whether these mutations play any role in patients with EC and GC. Therefore, in the same way as in the field of NSCLC and CRC, studies in patients with GC and EC should incorporate these transcriptional profiling endpoints.
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Angiogenesis inhibitors |
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Bevacizumab has demonstrated a survival advantage when added to irinotecan-, oxaliplatin- and 5-fluorouracil-based chemotherapy schedules in patients with advanced CRC [3841
], not only in the first-line setting but also in a refractory population. A vast development program including phase II and III studies with other irinotecan- and oxaliplatin-based schedules is ongoing in order to establish the role of bevacizumab and other anti-VEGF treatments, both in the first-line setting of patients with advanced CRC and in the adjuvant setting after radical surgery of locoregional colon cancer. Results of studies that address the efficacy of these compounds in pancreatic cancer and in GC are emerging. A phase II study in patients with advanced GC and GEJC with the combination of bevacizumab, cisplatin and irinotecan has been recently presented. Twelve out of 16 evaluable patients presented a PR (75%) [42
]. Although these results are very encouraging, randomized phase II and phase III studies are needed to demonstrate the clinical benefit of bevacizumab in this setting.
The anti-angiogenesis effects of VEGFR TKIs in GC have been demonstrated in different preclinical models. SU6668 has been shown to suppress peritoneal dissemination in an in vivo model with mice bearing TMK-1 human gastric tumors [43]. In another TMK-1 xenograft model, ZD6474 reduced tumor cell proliferation, increased tumor cell apoptosis and decreased microvessel density; these results show the capacity of some TKIs to target both angiogenesis and tumor growth signaling [44
]. Despite the existence of preclinical rationale for clinically exploring the activity of VEGFR TKIs, to date, no clinical data with these compounds in GC and EC has been presented.
Another scenario in the treatment of these malignancies is to combine drugs that target different pathways critical for the tumor growth. On this basis, a promising approach is the combination of drugs that target the EGFR pathway with drugs that target the angiogenesis process. There is some preclinical evidence that favors this approach: (a) the activation of EGFR by the ligands EGF or TGF- can upregulate the production of VEGF in cancer cells; (b) EGFR inhibition reduces VEGF production; and (c) resistance to EGFR inhibitors is associated with VEGF overexpression. The synergistic effects of targeting both the EGFR pathway and the angiogenesis pathway have been shown in some preclinical models. In an in vivo model with xenografts bearing TMK-1 human gastric tumors, the combination of cetuximab and DC101 (an anti-VEGFR mAb) showed a synergistic effect in tumor control [45
]. In a GEO human colon cancer xenograft model, the combination of cetuximab and a human VEGF antisense oligonucleotide showed a clear synergistic effect in tumor control [46
]. A randomized phase II combination study of either bevacizumab/cetuximab or bevacizumab/cetuximab/irinotecan was designed in patients with advanced CRC refractory to irinotecan-based chemotherapy. The preliminary results of this study (called BOND-2) were recently presented and, although there were no comparator arms with bevacizumab and cetuximab alone, the efficacy results in RR and median progression-free survival (PFS) were encouraging, suggesting a synergistic clinical effect targeting the two pathways [47
]. The same clinical approach warrants further evaluation in patients with EC and GC.
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Cell cycle inhibitors |
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Apoptosis promoters |
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Matrix metalloproteinase inhibitors |
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On the basis of these preclinical and clinical signs of activity, a phase III study was planned in patients with advanced GC and GEJC comparing marimastat versus placebo, with the primary objective being to demonstrate an advantage in the median OS for those patients allocated to receive marimastat [67]. A total of 369 patients were included in the study and they either had received previous 5-fluorouracil-based chemotherapy treatment (123 patients) or were chemo-naïve. The analysis of the population showed a median OS of 5.2 months and 4.5 months (hazard ratio 1.23, P = 0.07) and a 2-year OS of 9% and 3% (hazard ratio 1.27, P = 0.024) in the patients receiving marimastat and placebo, respectively. Although the primary objective of the study was not met, there was a clear trend for improvement of the median OS and a significant improvement of the 2-year OS figure in the patients treated with marimastat. When the analysis was limited to those patients that had previously received chemotherapy, there was a statistically significant improvement in the median OS (8.4 months versus 5.8 months, hazard ratio 1.53, P = 0.045) and in the 2-year OS (18% versus 5%, hazard ratio 1.68, P = 0.006) favoring the population that was treated with marimastat. There was also an advantage in the median and 2-year PFS in those patients treated with marimastat (hazard ratio 1.32, P = 0.009). Although this was the first demonstration of a therapeutic benefit for a MMPI in cancer patients, no further development of marimastat has been done in this population.
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Other targeted therapies |
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The p53 gene constitutes a major genetic alteration in most patients with GC. The key role played by the p53 gene product in the regulation of the cell cycle, cell proliferation and cell apoptosis has been widely studied. The most precise analysis of this genetic alteration is gene sequencing. However, analyzing this gene in large numbers of patients is cumbersome due to the fact that p53 mutations are spread across the gene. As a result of this, various surrogate tests have been designed to assess whether the gene is mutated or not. Most of these tests are prompted to evaluate the presence of a mutated P53 protein, but unfortunately, they have contradictory results. This has led to the generation of data that are not consistent and, therefore, not comparable [72]. Recent sequencing studies have shown that up to 35% of GC have p53 mutations, Indeed, the p53 mutation status is related to the GC subsite and the histological subtype: mutations were more frequent in cancers of the cardia than in cancers of the antrum and body (54% versus 25%, P = 0.005) and also more frequent in the intestinal type than in the diffuse type (42% versus 21%) [73
]. It is well known that tumors with p53 mutations are particularly resistant to chemotherapy. The resistance of these tumors to agents, such as camptothecin analogues, is based on the activation of the cell cycle checkpoint protein called Chk1, which induces permanent G2 phase cell cycle arrest without cell death. Several compounds have been identified as Chk1 or Chk1-induced cascade inhibitors [74
]. UCN-01, initially identified by the NCI drug screen panel as a CDK inhibitor, has recently been considered as a Chk1 inhibitor [75
]. In preclinical models, UCN-01 has been demonstrated to enhance the induction of apoptosis by irinotecan. Unfortunately, the systemic clinical toxicity related to UCN-01 administration may prevent complete clinical development. Fortunately other Chk1 inhibitors are currently in clinical development, and it is anticipated that these compounds will be evaluated in p53-mutated neoplasms such as CRC and GC.
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Conclusions |
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Received for publication April 24, 2005. Accepted for publication April 27, 2005.
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