RSSExploring biomarkers in head and neck cancer.
Source
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. corey.langer@uphs.upenn.edu.
Abstract
Personalized medicine based on predictive markers linked to drug response, it is hoped, will lead to improvements in outcomes and avoidance of unnecessary treatment in squamous cell carcinoma of the head and neck (SCCHN). Recent research has shown that expression of ERCC1 may predict resistance to treatment with platinum agents. Future testing for this marker may help select the optimal type of chemotherapy. Infection with human papillomavirus (HPV) is associated with less aggressive disease and better prognosis in locally advanced SCCHN treated with chemoradiation or radiation alone; HPV-positive patients may ultimately benefit from less intensive, less toxic therapy. K-RAS mutations, occurring in about 40% of colorectal cancers and associated with lack of benefit from epidermal growth factor receptor (EGFR) antibodies in this disease, are found in <5% of SCCHN patients, making routine testing for K-RAS mutations unwarranted at this time. Virtually all head and neck tumors overexpress EGFR, which limits the usefulness of EGFR expression as a marker for treatment selection. Although the incidence of EGFR tyrosine kinase domain mutations is very rare, a better understanding of the role of EGFR mutations, expression, amplification, and downstream effects in SCCHN may help define the role of EGFR in this setting. These observations caution against extrapolating results obtained with biomarkers in other types of cancer to SCCHN. Validation of each biomarker in the context of SCCHN clinical trials will be required before a specific marker can be incorporated into daily practice. Cancer 2012;. © 2012 American Cancer Society.
Copyright © 2012 American Cancer Society.
- PMID:
- 22281752
- [PubMed - as supplied by publisher]
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.
Source
1] Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2].
Abstract
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.
- PMID:
- 22281684
- [PubMed - as supplied by publisher]
EGFR-TKI resistant non-small cell lung cancer (NSCLC): New developments and implications for future treatment.
Source
Medical Center II, Department of Hematology/Oncology, Schwarzwald-Baar Clinic, Academic Teaching Hospital University of Freiburg, Villingen-Schwenningen, Germany.
Abstract
Treatment with receptor-tyrosine kinase inhibitors (TKIs) has improved progression-free and overall survival in patients with advanced non-small cell lung cancer (NSCLC). One major target for treatment with TKI is the epidermal growth factor receptor (EGFR), particularly in patients harboring activating mutations. However, despite initial responses and long lasting remissions, the development of secondary resistance inevitably leads to treatment failure. Analyzing recent data from various phase II/III trials it seems obvious that the single mode of action of gefitinib or erlotinib can provide temporary success only. Both preclinical and clinical evidence suggest that irreversible TKIs such as afatinib or PF00299804, or combined approaches using multiple kinase inhibition (e.g. EGFR and MET) and vertical inhibition by combination of small molecules and antibodies, seem to be more promising and will be the prevailing concepts to overcome secondary EGFR-TKI resistance for the near future.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
- PMID:
- 22281074
- [PubMed - as supplied by publisher]
PAR-1-dependent and PAR-independent pro-inflammatory signalling in human lung fibroblasts exposed to thrombin.
Source
Centre for Respiratory Research, University College London, United Kingdom.
Abstract
Proteinase-activated receptors (PARs) are crucial in orchestrating cellular responses to coagulation proteinases, such as thrombin and FXa. Four PARs have been characterized and have been shown to be differentially expressed in mice and humans and between tissues. We have previously shown that in murine lung fibroblasts, PAR-1 is solely responsible for all cellular responses to thrombin and FXa. In contrast, we report here that in primary human lung fibroblasts, known PARs fail to account for all of the cellular responses to thrombin, in particular in the presence of high, but physiologically achievable concentrations of thrombin. We report that primary human lung fibroblasts secrete CCL2 in a PAR-1-dependent manner at low thrombin concentration (∼ 0.3 nM). At or above 10 nM thrombin, pharmacological antagonism (RWJ-58259) fails to block thrombin-induced CCL2 release; whereas PAR-1 cleavage-blocking monoclonalantibodies (ATAP2 and WEDE15) only partially inhibit thrombin-induced CCL2 secretion. In addition, activation of PAR-3, PAR-4 and transactivation of either PAR-2 or EGFR were ruled out as being responsible for thrombin-mediated CCL2 secretion at high yet standard concentrations of the proteinase. We further provide evidence that PAR-1-dependent and PAR-independent signaling involves the rapid phosphorylation of ERK which in turn is absolutely required for thrombin-induced CCL2 secretion at both low and standard concentration of the proteinase. Our findings suggest the existence of a PAR-independent signaling mechanism in human lung fibroblasts and have important implications for the design of therapeutic strategies aimed at blocking pro-inflammatory signaling responses associated with excessive thrombin generation. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
Single Domain Antibodies: A New Concept for Epidermal Growth Factor Receptor and EGFRvIII Targeting.
Source
Endocrine and Metabolism Research Center, Tehran University of Medical Sciences , Tehran, Islamic Republic of Iran .
Abstract
Epidermal growth factor receptor (EGFR) is one of the major molecular targets for cancer diagnosis and therapy. EGFRand EGFRvIII, mutated form of EGFR, have been identified as participating in pathogenesis of some forms of human cancers. Monoclonal antibodies (mAbs) targeting EGFR/EGFRvIII have been shown to suppress the signal transduction pathways controlling tumor cell growth, proliferation, and apoptosis. Until now, different types of mAbs or antibodyfragments against EGFR family have been established. Some of these antibodies have been used clinically for treating various forms of human malignancies. More recently, a single domain antibody (sdAb) targeting this family of receptors has been introduced. The heavy chain antibodies (HCAbs) that made up variable regions of heavy chain, CH2, and CH3 domains are shown in camelids. SdAbs derived from camel HCAbs are the smallest known natural building parts for binding to antigen. They also possess a longer antigen recognizing region, which increases their capability for being more specific in target antigen enhancement. Camelid antibodies are highly valuable for their special characteristics, including heat resistance, small size, high solubility in an aqueous environment, and non-immunogenicity in a human environment. Due to these abilities, research on biotechnological production and treatment applications of recombinant smaller fragments of these only HCAbs is widely in progress. In this article, we will discuss the challenges and successes of different types of mAbs targeting EGFR/EGFRvIII in human cancer.
Colloidal Stability of Gold Nanoparticles Modified with Thiol Compounds, Bioconjugation and Application in Cancer Cell Imaging.
Abstract
Gold nanoparticles (GNPs) are attractive alternative optical probes and good biocompatible materials due to their special physical and chemical properties. However, GNPs have a tendency to aggregate particularly in the presence of certain biological molecules such as nucleic acids and proteins. How to improve the stability of GNPs and their bioconjugates in aqueous solution is a critical issue in the bioapplications. In this study, we first synthesized 17 nm GNPs in aqueous solution and then modified them with six thiol compounds including glutathione, mercaptoproconic acide (MPA), cysteine, cystamine, dihydrolipoic acid (DHLA) and thiol-ended polyethylene glycol (PEG-SH) via Au-S bond. We systematically investigated the effects of thiol ligands, buffer pH and salt concentrations of solution on colloidal stability to GNPs using UV-Vis absorption spectroscopy. We found that GNPs modified with PEG-SH were the most stable in aqueous solution compared to other thiol compounds. Based on the results above, we developed a simple and efficient approach for modification of GNPs using a mixture of PEG-SH and MPA as ligands. This bi-ligands modified GNPs were facilely conjugated to antibody using EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) as linkage reagent. We conjugated GNPs to epidermal growth factor receptor (EGFR) antibodies, and successfully used the antibody-GNPs conjugates as targeting probes for imaging of cancer cells using the illumination of dark field. Compared to current methods for modification and conjugation of GNPs, our method described here showed simple, low-cost, and have potential applications in bioassays and cancer diagnostics and studies.
Decreased Autocrine EGFR Signaling in Metastatic Breast Cancer Cells Inhibits Tumor Growth in Bone and Mammary Fat Pad.
Source
Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana, United States of America.
Abstract
Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01), reduced osteolytic lesion tumor volume (p<0.01), increased survivorship in vivo (p<0.001), and resulted in decreased MDA-231 growth in the fat pad (p<0.01). Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1) and matrix metalloproteinase 9 (MMP9), both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.
Suppression of the Epidermal Growth Factor Receptor Inhibits Epithelial-Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells.
Source
Department of General Surgery, Peking University First Hospital, 8th Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
Abstract
BACKGROUND:
Aberrant expression of epidermal growth factor receptor (EGFR) has been detected in pancreatic cancer; however, the mechanisms of EGFR in inducing pancreatic cancer development have not been adequately elucidated. The objective of this study was to determine the role of EGFR in mediating epithelial-mesenchymal transition (EMT) in pancreatic cancer cells.
METHODS:
Pancreatic cancer cell line PANC-1 was transfected with small interfering RNA of EGFR by use of a lentiviral expression vector to establish an EGFR-knockdown cell line (si-PANC-1). PANC-1 cells transfected with lentiviral vector expressing negative control sequence were used as negative control (NC-PANC-1). Scratch assay and transwell study were used to analyze cell migration and invasion. Real-time PCR and Western blotting were used to detect the expression of EMT markers E-cadherin, N-cadherin, vimentin, and fibronectin and transcription factors snail, slug, twist1, and sip1 in PANC-1, NC-PANC-1, and si-PANC-1 cells. Immunofluorescent staining with these antibodiesand confocal microscopy were used to observe their cellular location and morphologic changes.
RESULTS:
After RNA interference of EGFR, the migration and invasion ability of si-PANC-1 cells decreased significantly. The expression of epithelial phenotype marker E-cadherin increased and the expression of mesenchymal phenotype markers N-cadherin, vimentin, and fibronectin decreased, indicating reversion of EMT. We also observed intracellular translocation of E-cadherin. Expression of transcription factors snail and slug in si-PANC-1 cells decreased significantly.
CONCLUSION:
Suppression of EGFR expression can significantly inhibit EMT of pancreatic cancer PANC-1 cells. The mechanism may be related with the down-regulation of the expression of transcription factors snail and slug.
Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer.
Source
1] Department of Medical Oncology, Hospital del Mar, Barcelona, Spain. [2] Cancer Research Program, Institut Municipal d'Investigació Médica (IMIM, Hospital del Mar Research Institute), Barcelona, Spain. [3].
Abstract
Antibodies against epidermal growth factor receptor (EGFR)-cetuximab and panitumumab-are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquiredEGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.
Targeting EGFR for Treatment of Glioblastoma: Molecular Basis to Overcome Resistance.
Source
Ludwig Institute for Cancer Research, La Jolla, CA, USA. wcavenee@ucsd.edu.
Abstract
Glioblastoma (glioblastoma multiforme; GBM; WHO Grade IV) accounts for the majority of primary malignant brain tumors in adults. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities encountered in GBM. A range of potential therapies that target EGFR or its mutant constitutively active form, ΔEGFR, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, and RNA-based agents, are currently in development or in clinical trials for the treatment of GBM. Data from experimental studies evaluating these therapies have been very promising; however, their efficacy in the clinic has so far been limited by both upfront and acquired drug resistance. This review discusses the current status of anti-EGFR agents and the recurrent problem of resistance to these agents that strongly indicates that a multiple target approach will provide a more favorable future for these types of targeted therapies in GBM.
- PMID:
- 22268382
- [PubMed - as supplied by publisher]
Treatment paradigms with epidermal growth factor receptor-targeted therapies in colorectal cancer.
Source
NYU Cancer Institute and Department of Medicine, New York University School of Medicine, NY.
Abstract
Epidermal growth factor receptor (EGFR) has been validated as an important target in the treatment of metastatic colorectal cancer (mCRC). While initial studies focused on the treatment of disease that was refractory to available chemotherapy agents, 2 recent themes have emerged: the use of KRAS mutation status to select those who will benefit from anti-EGFR therapy, and the movement of these agents to earlier "lines" of therapy. We review the use of theEGFR-targeted monoclonal antibodies cetuximab and panitumumab in mCRC including the incorporation of KRAS testing in patients, and also review the use of prophylactic therapy for skin toxicity associated with EGFR-targeted therapies.
Epidermal Growth Factor Receptor-Targeted Photosensitizer Selectively Inhibits EGFR Signaling and Induces Targeted Phototoxicity In Ovarian Cancer Cells.
Source
Wellman Center for Photomedicine, Department of Dermatology (Bartlett Hall 314), Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA.
Abstract
Targeted photosensitizer delivery to EGFR expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyin monoacid ring A (BPD) was coupled to anEGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of theantibody.
Copyright © 2012. Published by Elsevier Ireland Ltd.
Requirement of matrix metalloproteinase-1 for intestinal homeostasis in the adult Drosophila midgut.
Source
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Abstract
Stem cells are tightly regulated by both intrinsic and extrinsic signals as well as the extracellular matrix (ECM) for tissue homeostasis and regenerative capacity. Matrix metalloproteinases (MMPs), proteolytic enzymes, modulate the turnover of numerous substrates, including cytokine precursors, growth factors, and ECM molecules. However, the roles of MMPs in the regulation of adult stem cells are poorly understood. In the present study, we utilize the Drosophila midgut, which is an excellent model system for studying stem cell biology, to show that Mmp1 is involved in the regulation of intestinal stem cells (ISCs). The results showed that Mmp1 is expressed in the adult midgut and that its expression increases with age and with exposure to oxidative stress. Mmp1 knockdown or Timp-overexpressing flies and flies heterozygous for a viable, hypomorphic Mmp1 allele increased ISC proliferation in the gut, as shown by staining with an anti-phospho-histone H3 antibody and BrdU incorporation assays. Reduced Mmp1 levels induced intestinal hyperplasia, and the Mmp1depletion-induced ISC proliferation was rescued by the suppression of the EGFRsignaling pathway, suggesting that Mmp1 regulates ISC proliferation through the EGFR signaling pathway. Furthermore, adult gut-specific knockdown and whole-animal heterozygotes of Mmp1 increased additively sensitivity to paraquat-induced oxidative stress and shortened lifespan. Our data suggest that Drosophila Mmp1 is involved in the regulation of ISC proliferation for maintenance of gut homeostasis.
Copyright © 2012. Published by Elsevier Inc.
Highly sensitive SERS detection of cancer proteins in low sample volume using hollow core photonic crystal fiber.
Source
Bio-Optical Imaging Group, Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR), 11 Biopolis Way, Singapore 138667, Singapore.
Abstract
Enzyme-linked immunosorbent assays (ELISA) are commonly used for detecting cancer proteins at concentration in the range of about ng-μg/mL. Hence it often fails to detect tumor markers at the early stages of cancer and other diseases where the amount of protein is extremely low. Herein, we report a novel photonic crystal fiber (PCF) based surface enhanced Raman scattering (SERS) sensing platform for the ultrasensitive detection of cancer proteins in an extremely low sample volume. As a proof of concept, epidermal growth factor receptors (EGFRs) in a lysate solution from human epithelial carcinoma cells were immobilized into the hollow core PCF. Highly sensitive detection of protein was achieved using anti-EGFR antibody conjugated SERS nanotag. This SERS nanotag probe was realized by anchoring highly active Raman molecules onto the gold nanoparticles followed by bioconjugation. The proposed sensing method can detect low amount of proteins at ∼100pg in a sample volume of ∼10nL. Our approach may lead to the highly sensitive protein sensing methodology for the early detection of diseases.
Copyright © 2012 Elsevier B.V. All rights reserved.
Treatment of advanced non small cell lung cancer.
Source
Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy.
Abstract
Lung cancer is the major cause of cancer death in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis; the majority of patients will be diagnosed with non operable, advanced-stage disease. Palliative chemotherapy and/or radiotherapy represent the standard of care of this disease. Platinum based doublets with third generation agents are considered the standard of first line advanced NSCLC treatment. However, data arising from the availability of pemetrexed suggest that histology could play a key role in decision making. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for therapeutic agents. Bevacizumab is the first recombinant humanized monoclonal antibody (mAb) binding VEGF to demonstrate clinical benefit and a rather survival prolongation in combination with chemotherapy in the treatment of non squamous chemo-naive advanced NSCLC patients. Two types of anti-EGFR targeting agents have reached advanced clinical development: mAbs and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib has been tested in several phase II-III studies showing an improvement in survival and responses in first, second and third line treatment in selected patients with specific clinical and molecular characteristics. Furthermore, erlotinib has showed to significantly improve survival in an unselected population of patients following the failure of one or two chemotherapy regimens. This review will discuss the different therapeutic options for first and second line treatment in the clinical practice.
[Construction and immunological analysis of a combined multi-epitope vaccine against EGFR/HER2].
Source
Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing 210028, China.
Abstract
A recombinant plasmid pET28a-HBcAg-delta n was constructed, in which three mimic B-epitopes of HER family were inserted into the truncated HBc vector. The fusion protein expressed was purified and used to immunize BALB/c mice to induce antibody against the epitopes. Three mimic epitope genes were inserted into the sequences of amino acid residues 78 and 79 of HBcAg by overlap PCR. The PCR product was then cloned into pET28a to construct recombinant expression plasmid which was transformed to E. coli BL21 (DE3) and induced by IPTG. After purification, the fused protein designed HBHE was used to immunize BALB/c mice to detect humoral immunoresponse. The recombinant plasmid was successfully constructed by DNA sequencing analysis. A fusion protein with correct molecular mass was expressed and confirmed by SDS-PAGE. High titre antibody was elicited in the mice immunized with HBHE by indirect ELISA and Western blotting. The HBc particle vector containing three B-epitopes of HER family had been successfully prepared, purified and high titre antibody against HBHE was detected. All these data are helpful in further research of the broad-spectrum anti-tumour effect of combine polypeptide epi-position vaccine of EGFR and HER2.
- PMID:
- 22260023
- [PubMed - in process]
[The role of chemotherapy and targeted antiVEGF- and antiEGFR-therapy in metastatic colorectal cancer: a case report of long-term and intensive response].
Source
Klinika komplexní onkologické péce, Masarykův onkologický ústav, Brno. nemecek@mou.cz
Abstract
BACKGROUNDS:
Colorectal cancer (CRC) is the second most frequent malignancy in the Czech Republic. Treatment of a metastatic disease is based on application of palliative chemotherapy (fluorouracil, leucovorin, irinotecan, oxaliplatin). When combined with targeted agents against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), it can result in significant and long-term response.
CASE:
We present a case of a 34-years old man with adenocarcinoma of sigmoid colon (Dukes C) with 5 years disease-free survival (DFS) after primary surgery (in 2002) and adjuvant chemotherapy with FOLFIRI (12 cycles). A solitary relapse in retroperitoneal lymph nodes in November 2007 was treated with retroperiotoneal dissection followed by adjuvant chemotherapy with FOLFOX 4 (12 cycles) and targeted radiotherapy of retroperitoneal area (completed in May 2008). An early relapse occurred one month later (June 2008--infraclavicular area, thoracic wall and retroperitoneal lymph nodes), patient underwent first line palliative chemotherapy with XELIRI + bevacizumab leading to partial remission (PR) after 3 months and complete remission (CR) after 6 months of treatment. Bevacizumab monotherapy was continued for the next 8 months up to March 2010, when a progression in the lung occurred. After wild-type status was confirmed, KRAS treatment was changed to the second line combination of irinotecan and cetuximab that resulted in nearly complete remission after 6 months and preservation of this remission after the next 6 months of cetuximab monotherapy. All treatments were well tolerated with good quality of life.
CONCLUSION:
Our case demonstrates the current options in the treatment of metastatic CRC. There is a trend to gradually use all the above listed cytostatics in combination with anti-VEGF and anti-EGFR monoclonal antibodies. When administered early, it may provide a significant and long-term treatment response.
- PMID:
- 22257237
- [PubMed - in process]
New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Source
Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 850, Chicago, IL, 60611-2942, USA, m-agulnik@northwestern.edu.
Abstract
Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN.
Clinical and Economic Aspects of KRAS Mutational Status as Predictor for Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer Patients.
Source
Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna), LB Cluster Translational Oncology, 3rd Medical Department, Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria.
Abstract
Treatment of metastasized colorectal cancer (mCRC) patients with anti-epidermal growth factor receptor (EGFR)-directed monoclonal antibodies is driven by the results of the KRAS mutational status (wild type [WT]/mutated [MUT]). To find out as to what extent the treatment selection based on the KRAS status had impact on overall costs, a retrospective analysis was performed. Of 73 mCRC patients 31.5% were MUT carriers. Costs of EGFR inhibitor treatment for WT patientswere significantly higher compared to those for patients with MUT (p = 0.005). Higher treatment costs in WT carriers reflect a significantly higher number of treatment cycles (p = 0.012) in this cohort of patients. Savings of drug costs minus the costs for the determination of KRAS status accounted for EUR 779.42 (SD ±336.28) per patient per cycle. The routine use of KRAS screening is a cost-effective strategy. Costs of unnecessary monoclonal EGFR inhibitor treatment can be saved in MUT patients.
Copyright © 2012 S. Karger AG, Basel.
Cetuximab inhibits the growth of mucinous ovarian carcinoma tumor cells lacking KRAS gene mutations.
Source
Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
Abstract
The purpose of this study was to explore the possibility of targeted molecular therapy with anti-epidermal growth factor receptor (anti-EGFR) antibody (cetuximab) for the treatment of mucinous ovarian carcinoma. We analyzed EGFR protein expression and KRAS gene mutations in 5 mucinous ovarian carcinoma cell lines RMUG-L, RMUG-S, MN-1, OMC-1 and MCAS and evaluated the in vitro and in vivo effects of cetuximab on each. EGFR expression was observed in all cell lines except for MN-1 cells, and a KRAS gene mutation at codon 12 was detected only in the MCAS cell line. Cetuximab inhibited RMUG-L and OMC-1 cell growth in vitro and completely blocked RMUG-L tumor growth in vivo. On the other hand, cetuximab did not affect MCAS cell growth in vitro and only partially reduced the MCAS tumor growth in vivo. These results suggest the possibility of targeted molecular therapy with cetuximab for mucinous ovarian carcinoma cells lacking a KRAS gene mutation.
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