- (2006) Volume 7, Issue 3
Raffaele Pezzilli, Lorenzo Fantini
Department of Internal Medicine, Sant'Orsola-Malpighi Hospital. Bologna, Italy
Antibodies, Monoclonal; Gemcitabine; Pancreatic Neoplasms; Receptor, Epidermal Growth Factor
In the past, most of the knowledge gained regarding the physiology and the pathology of the pancreas has been evaluated in experimental studies on animals especially on rats/mice. This approach has been criticized in recent years because most of the data obtained from animals cannot be fully applied to humans [1]. A new approach to the physiology and pathology of the pancreas comes from studying its molecular biology, and the results obtained seem to be more reliable than those obtained in animals. An example of this assumption comes from studies on pancreatic ductal adenocarcinoma: this cancer seems to result from a progressive accumulation of mutations in genes such as K-ras, CDKN2A, p53, BRCA2, p164ink, and SMAD4 [2]; in particular, the SMAD4 mutations which result in the constitutive activation of transforming growth factor b1 signalling, are generally considered to be responsible for the desmoplastic response, which includes upregulated expression of the extracellular matrix, and type I collagen [3, 4, 5, 6]. Grzesiak et al. [7, 8] have also shown that a2b1 integrin-mediated adhesion on type I collagen promotes a malignant phenotype in FG pancreatic cells, as defined by increased proliferation and haptokinetic cell migration, downregulated expression and localization of E-cadherin and b-catenin in cell-cell contacts, increased phosphorylation of GSK3b and PKB/Akt, and downregulated expression of PTHrP, IL-6, and IL-8 as compared to fibronectin, type IV collagen, laminin, or vitronectin. These results are in agreement with previous studies demonstrating that type I collagen downregulates E-cadherin expression in Panc-1, BxPC-3, and PaTu8988s pancreatic cancer cells, resulting in increased proliferation and migration compared to fibronectin. Recently, the same group of researchers demonstrated similar phenotypic differences in BxPC-3, Colo-357, and CFPAC cells on type I collagen as compared to fibronectin; that is, increased haptokinetic cell migration, downregulated expression and localisation of E-cadherin and b-catenin in disrupted cell-cell contacts, increased phosphorylation of GSK3 and PKB/Akt, and decreased expression of PTHrP, IL-6, and IL-8. Furthermore, functional studies with pharmacological inhibitors for GSK3 and PKB/Akt suggest that these signalling effectors are involved in the mechanism of a2b1 integrin-mediated regulation of the malignant phenotype in FG cells. Type I collagen, in particular, seems to play an active role in vitro and in vivo in the pathophysiology of pancreatic cancer [9, 10] as demonstrated by in vitro studies which have shown how pancreatic cancer cell lines stimulate the production of type I collagen from adjacent stellate cells, which resulted in increased cancer cell proliferation and resistance to chemically induced apoptosis. However, the integrin specificity of this interaction between tumor cells and type I collagen was not identified. Thus, Grzesiak and Bouvet [11] examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. They have shown that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilizing function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, they further demonstrated that the malignant phenotype on type I collagen is mediated specifically by the a2b1 integrin. These results identify a2b1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.
The main utility of molecular studies for clinicians is the introduction of new agents for controlling pancreatic cancer progression into clinical practice. One example is the finding that altered expression or constitutive activation of the epidermal growth factor receptor (EGFR/HER1/erbB1) commonly occurs in both primary and metastatic pancreatic cancers and is often a critical component in progressive growth and resistance to normal mechanisms of cell death [12, 13, 14]. Epidermal growth factor receptor expression in pancreatic cancer has been correlated with tumor aggressiveness [15]. On the basis of this information, it has been found that matuzumab, a humanised immunoglobulin G1 (IgG1) monoclonal antibody to the human EGFR binds the EGFR with high affinity, competitively blocking natural ligand binding and blocking receptor-mediated downstream signalling. In preclinical studies, matuzumab demonstrated activity in the PAXF546 xenograft model of human pancreatic cancer which expressed high levels of EGFR and demonstrated almost complete resistance to clinically available chemotherapeutic drugs. Also, combining matuzumab with gemcitabine enhanced the effects of gemcitabine in a model of gemcitabine-sensitive pancreatic cancer and antitumor effects were mediated by both direct inhibition of tumor growth and inhibition of tumor-induced angiogenesis. In addition, because matuzumab is an IgG1 antibody to the EGFR capable of mediating antibody-dependent cellular cytotoxicity, additional cytotoxic mechanisms may be involved in its effects on pancreatic cancer. A phase I clinical trial with matuzumab demonstrated that it is well-tolerated as a single agent [16]; it blocks growth factor signalling through EGFR with a weekly dose of 800 mg and the dose-limiting toxicities occurred at 2,000 mg on a weekly schedule consisting of headache and fever. Skin reactions, a common effect of anti-EGFR, also occur with matuzumab, but they are less severe than those of the other anti-EGFR agents. The results of a phase I study for assessing the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine have recently been communicated [17]. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients received increasing doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1,000 mg/m2 weekly in weeks 1-3 of each 4- week cycle). The results of this study have shown that severe treatment-related toxicities were limited to grade 3 neutropenia, leucopenia, and a decreased white blood cell count. Common drug-related adverse events were skin toxicities and fever. Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction, the effects being seen even in the lowestdose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response or stable disease occurred in 66.7% of the treated patients, with three partial responses among six patients evaluated in the group receiving 800 mg weekly. In conclusion, matuzumab seems to be well tolerated in biologically effective doses with standard gemcitabine therapy; the combination is feasible and may have enhanced activity.
In summary, we hope that the search for new antitumoral strategies will be carried out on cellular lines rather than on animals; this approach seems to be better and easier for applying the positive results to humans.
