Factor Receptor Monoclonal Antibody Cetuximab Research Articles

Targeting Treatment Resistance in Head and Neck Cancer through Unravelling Molecular Mechanisms

Head and neck cancer is a common malignancy worldwide and carries a poor prognosis when it is diagnosed late. Treatment itself often carries significant morbidity and impairs quality of life. There have been few actionable targets for squamous cell carcinoma of the head and neck, notably anti-epidermal growth factor receptor monoclonal antibody cetuximab and antiPD1 immunotherapy that have reached clinical use. We studied a polymorphism in the extracellular semaphorin domain of C-MET in the context of SCC head/neck and lung, uncovering a novel mechanism conferring biological aggressiveness and potential for therapeutic intervention. TP53 mutations are the most common somatic mutations in SCCHN and we studied the gain of function mutation p53R158G in the S4 strand of the DNA binding domain, uncovering the mechanism of carcinogenicity. In South East Asia including Malaysia and Singapore, nasopharyngeal carcinoma is associated with EBV and is the commonest head and neck malignancy, with a propensity for recurrence and metastases. We have interest in development of anti-vascular endothelial growth factor therapy as a means to overcome treatment resistance, and some of this work will be described in this presentation.

High prevalence of severe hypovitaminosis D in patients with advanced gastric cancer treated with first-line chemotherapy with or without anti-EGFR–directed monoclonal antibody (EXPAND trial) showing no prognostic impact

PurposeThe goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab. MethodsSix hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms. ResultsMajority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti–epidermal growth factor receptor monoclonal antibody cetuximab. ConclusionsAlthough majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy.

Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type K-RAS Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial

The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.

A phase II study for metabolic in vivo response monitoring with sequential 18FDG-PET-CT during treatment with the EGFR-monoclonal-antibody cetuximab in metastatic colorectal cancer: the Heidelberg REMOTUX trial

BackgroundThe epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in 18 F-Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes.Methods/designThe REMOTUX trial is an investigator-initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first 18 F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second 18 F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri-cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment.DiscussionThe aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible.Trial registrationClinicalTrials.gov NCT200811021020; EudraCT 200901327923

Genetic Polymorphisms of FcγRIIa and FcγRIIIa Are Not Predictive of Clinical Outcomes after Cetuximab plus Irinotecan Chemotherapy in Patients with Metastatic Colorectal Cancer

Objective: The anti-epidermal growth factor receptor monoclonal antibody cetuximab has been shown to be effective in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Fragment C γ receptor (FcγR) polymorphisms may predict the effectiveness of cetuximab, but this has not been established. This study investigated the clinical relevance of FcγR gene polymorphisms and KRAS status in iri-notecan-refractory mCRC patients treated with cetuximab. Methods: The total number of irinotecan-refractory mCRC patients studied was 118. Among them, 117 and 107 patients were screened for KRAS mutations and genetic polymorphisms of FcγRIIa-131H/R and FcγRIIIa-158V/F, respectively. The association of FcγR polymorphisms and KRAS mutations with clinical outcome was analyzed. Results:KRAS mutations were found in 33 patients (27.1%). Wild-type KRAS was associated with a better response rate (p < 0.001), longer progression-free survival (p < 0.001) and longer overall survival (p < 0.001). FcγRIIa H/H, H/R and R/R polymorphisms were observed in 54, 49 and 4 patients, respectively, and FcγRIIIa V/V, V/F and F/F polymorphisms were observed in 6, 65, and 36 patients, respectively. Clinical outcomes were not significantly associated with either FcγRIIa or FcγRIIIa polymorphisms or with combinations of KRAS status and FcγR polymorphisms. Conclusion: The FcγRIIa and FcγRIIIa polymorphisms may not be useful molecular biomarkers for the activity of cetuximab in patients with mCRC.

Radiosensitization induced by the anti-epidermal growth factor receptor monoclonal antibodies cetuximab and nimotuzumab in A431 cells

Epidermal growth factor receptors (EGFR) are overexpressed in a wide range of malignancies including head and neck, colon, and breast cancers. It has been identified that carcinomas with high expression levels of EGFR are more resistant to radiotherapy. Therefore, inhibiting nuclear translocation of EGFR to increase the radiosensitivity of malignant cells expressing EGFR offers the potential for increasing the therapeutic index of radiotherapy. The purpose of the present study was to quantify and to compare the radiosensitizing properties of the well-known anti-EGFR antibodies, cetuximab and nimotuzumab in human epidermoid A431 overexpressing EGFR cells. Cells were treated with two concentrations of the antibodies and then irradiated with a single dose of 4 Gy. The results indicated that the two antibodies induced radiosensitization increasing the percentage of dead/dying cells and the yield of γ-H2AX foci 24 h after irradiation. Whereas cetuximab exhibited a significant increase in radiosensitization at the highest concentration, the effects of nimotuzumab were more modest. A correlation between γ-H2AX foci signals and dead/dying cells was observed. The disparity in modulation of radiation-induced DNA damage by the two antibodies could be associated with the level of their respective intrinsic cytotoxic properties. Overall, the findings highlight the potential therapeutic benefit of combination therapy with anti-EGFR antibodies and radiotherapy for relevant carcinomas.

Anti-Egfr Therapy in Colorectal Cancer: How to Choose The Right Patient

The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.

Requirement of hypoxia-inducible factor-1α down-regulation in mediating the antitumor activity of the anti–epidermal growth factor receptor monoclonal antibody cetuximab

We tested our novel hypothesis that down-regulation of hypoxia-inducible factor-1alpha (HIF-1alpha), the regulated subunit of HIF-1 transcription factor that controls gene expression involved in key functional properties of cancer cells (including metabolism, survival, proliferation, invasion, angiogenesis, and metastasis), contributes to a major antitumor mechanism of cetuximab, an approved therapeutic monoclonal antibody that blocks activation of the epidermal growth factor receptor. We showed that cetuximab treatment down-regulates HIF-1alpha levels by inhibiting synthesis of HIF-1alpha rather than by enhancing degradation of the protein. Inhibition of HIF-1alpha protein synthesis was dependent on effective inhibition of the phosphoinositide-3 kinase (PI3K)/Akt pathway by cetuximab, because the inhibition was prevented in cells transfected with a constitutively active PI3K or a constitutively active Akt but not in cells with a constitutively active MEK. Overexpression of HIF-1alpha conferred cellular resistance to cetuximab-induced apoptosis and inhibition of vascular endothelial growth factor production in sensitive cancer cell models, and expression knockdown of HIF-1alpha by RNA interference substantially restored cellular sensitivity to the cetuximab-mediated antitumor activities in experimental resistant cell models created by transfection of an oncogenic Ras gene (G12V) or by concurrent treatment of the cells with insulin-like growth factor-I. In summary, our data show that cetuximab decreases HIF-1alpha protein synthesis through inhibition of a PI3K-dependent pathway and that an effective down-regulation of HIF-1alpha is required for maximal therapeutic effects of cetuximab in cancer cells.

Abnormal Hair Growth in a Patient With Head and Neck Cancer Treated With the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab

Abnormal Hair Growth in a Patient With Head and Neck Cancer Treated With the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab

Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck

To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.

The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

We have previously shown that the antiepidermal growth factor receptor monoclonal antibody cetuximab (C225; Erbitux), which was recently approved for the treatment of metastatic colorectal cancer, has antiangiogenic properties, inhibiting vascular endothelial growth factor (VEGF) secretion in culture and in animal models. Here, we have furthered the study by demonstrating that cetuximab reduces cellular levels of hypoxia-inducible factor-1 alpha (HIF-1alpha), a transcriptional regulator of VEGF expression, in A431 epidermoid carcinoma cells under both normoxic and hypoxic culture conditions. Expression of a constitutively active Ras in A431 cells rendered cellular resistance to the cetuximab-mediated reduction of the HIF-1alpha level. Cell lines with naturally occurring phosphatase and tensin homologue deleted on chromosome 10 mutations or deletions were also resistant to cetuximab-mediated reduction of the HIF-1alpha level. Pharmacologic inhibition of phosphatidylinositol 3-kinase with LY294002 reduced the HIF-1alpha level in both normoxic and hypoxic A431 cells, whereas inhibition of the mitogen-activated protein kinase kinase by PD98059 reduced the level of HIF-1alpha only in normoxic A431 cells. In addition, cetuximab reduced the cellular level of HIF-1alpha in the presence of a proteasome inhibitor, lactacystin, indicating that cetuximab acts mainly at the level of protein synthesis. The reduction of HIF-1alpha in response to cetuximab treatment was accompanied by transcriptional inhibition of VEGF expression, measured by a luciferase assay in A431 cells transfected with a vector containing the VEGF hypoxia response element. Taken together, our results indicate that the previously demonstrated inhibition of VEGF by cetuximab occurs at the level of transcription in response to a reduced level of HIF-1alpha and justify further testing of therapeutic strategies that combine cetuximab with approaches inhibiting the function of VEGF or the VEGF receptor.

Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab Augments Radiation Effects in Glioblastoma Multiforme in Vitro and in Vivo

Previously, we demonstrated that the anti-epidermal growth factor receptor (EGFR) antibody cetuximab alone was effective against EGFR-amplified glioblastoma multiforme (GBM) cells in vivo and in vitro. The purpose of the present work was to study further the effectiveness of cetuximab as a monotherapy as well as combining it with radiation therapy or chemotherapy. EGFR-amplified GBM cells were implanted either in the flanks of nude mice to determine the effectiveness of cetuximab on larger tumor burden or intracranially to assess the ability of cetuximab to cross the blood-brain barrier. Cells were also exposed to cetuximab in combination with radiation in vivo or chemotherapeutic agents in vitro. Increasing tumor burden in the flanks of mice decreased the amount of tumor growth inhibition. For the first two intracranial models using cetuximab for 5 weeks, the treated mice had a significant increase in median survival compared with controls. When cetuximab was given indefinitely, the results were encouraging, with an increase in median survival for the treated group not yet reached but at least 900%. Mice with flank GBM exposed to cetuximab and radiation had a larger increase in median survival than those with either treatment alone. Preliminary in vitro experiments using cetuximab and chemotherapeutic agents showed increased cytotoxicity. These results were encouraging, demonstrating the effectiveness of cetuximab against EGFR-amplified GBM. Surprisingly, cetuximab was effective when administered systemically in an intracranial model. Radiation augmented the effect of cetuximab on GBM in vitro and in vivo. In vitro analysis demonstrated additive effects for chemotherapeutic agents as well. These results confirm EGFR blockade with cetuximab as a potential treatment against human GBM.

Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody cetuximab (IMC-C225) in combination with irinotecan (CPT-11), 5-FU, and leucovorin against human colorectal carcinoma xenografts

Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody cetuximab (IMC-C225) in combination with irinotecan (CPT-11), 5-FU, and leucovorin against human colorectal carcinoma xenografts

Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation

Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux (cetuximab) on human tumor cells expressing both EGFR and HER2. Investigation of the effect of cetuximab on the activation of EGFR-EGFR, EGFR-HER2 and HER2-HER2 homodimers and heterodimers was conducted using the NCI-N87 human gastric carcinoma cell line. Treatment of NCI-N87 cells with cetuximab completely inhibited formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. Activation of HER2-HER2 homodimers was not appreciably stimulated by exogenous ligand and was not inhibited by cetuximab treatment. Furthermore, cetuximab inhibited EGF-induced EGFR and HER2 phosphorylation in CAL27, NCI-H226 and NCI-N87 cells. The activation of downstream signaling molecules such as AKT, MAPK and STAT-3 were also inhibited by cetuximab in these cells. To examine the effect of cetuximab on the growth of tumors in vivo, athymic mice bearing established NCI-N87 or CAL27 xenografts were treated with cetuximab (1 mg, i.p., q3d). The growth of NCI-N87 and CAL27 tumors was significantly inhibited with cetuximab therapy compared to the control groups (p<0.0001 in both cases). In the CAL27 xenograft model, tumor growth inhibition by cetuximab treatment was similar to that by cetuximab and trastuzumab combination treatment. Immunohistological analysis of cetuximab-treated tumors showed a decrease in EGFR-HER2 signaling and reduced tumor cell proliferation. These results suggest that cetuximab may be useful in the treatment of carcinomas co-expressing EGFR and HER2.