Results of monoclonal antibodies against EGFR-receptors application in patients with metastatic colorectal cancer (mCRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14701-e14701
Author(s):  
Liubov Yu Vladimirova ◽  
Oleg Ivanovich Kit ◽  
Elena A Nikipelova ◽  
Natalya A Abramova
Keyword(s):  
Monoclonal Antibodies ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Wild Type ◽  
Symptomatic Medication ◽  
Significant Efficacy ◽  
Epidermal Growth ◽  
Bone Marrow Function ◽  
Abstract Submission ◽  
Egfr Receptors

e14701 Background: Monoclonal antibodies against the epidermal growth factor receptor(EGFR)are standard components of treatment in mCRC.This study was designed to evaluate the tolerability and efficacy of the combinations of Panitumumab(P) and Cetuximab(C) with chemotherapy in patients with wild type(WT) KRAS tumors mCRC. Methods: Mutation analysis of KRAS(codons12,13) was done on samples at diagnosis. Key elegibility criteria included measurable mCRC stage IV, ECOG ≤2, adequate liver,kidney and bone marrow function, no brain metastases. P was administered 6mg/ kg 1 day q2w. C was administered 400mg/m² 1day and 250mg/m² q1w. Combination with FOLFOX-6 or FOLFIRI pegimens was allowed. Endpoints include response rate, OS, PFS and safety. Results: Of 38 testable samples there were 21(55.3%) WT KRAS tumors. All of these 21 (13male and 8female) pts were recruited. Mean age was 58.1±12.3. Synchronous metastases had 33.3%(7pts). Majority of pts benefited from anti-EGFR combined with cytotoxic chemotherapy 80.9% (17), mostly FOLFIRI – 57,1%(12).There were23.8%(5) in the 1st line CT, 76.1%(16) in the 2nd line CT. 6 mos of the treatment were analyzed. Overall RR was76.1 %(16) including 6PR(28.5%) and 10SD(47.6%). Med OS= 9.1mo, Med PFS= 4.3mo. 8 pts(38.1%) are alive till the abstract submission. Most common toxicities were:skin rash 2/3Gd.-90.5%(19), xeroderma 2Gd.-42.9%(9),skin itch 1/3Gd.-42.9%(9), paronychia 2Gd. -14.2%(3), purulent psorophthalmia 2Gd.-14.2%(3). All kinds of toxicities were controlled by symptomatic medication if necessary and did not lead to anti-EGFR agents dalay. Besides,diarrhea 1/2Gd.- 66.7%(14), 3Gd.-14.3%(3), neutropenia 1/2Gd.-28.6%(6), 3/4Gd.-9.5%(2), nausea 3/4Gd.- 14.3%(3), vomiting 1/2Gd.- 42.9%(9), fatigue 1/2Gd.-47.6%(10). Conclusions: These results consider significant efficacy of anti-EGFR agents combined with CT in pts with mCRC. Controlled toxicity of the therapy allows to use it widely.

scholarly journals Resistance to anti-EGFR targeted therapy mediated by oncogenetic mutations in colorectal cancer: Revision of the dogma?

2020 ◽  
pp. 2-2
Keyword(s):  
Monoclonal Antibody ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Colorectal Carcinoma ◽  
Tumor Cells ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Epidermal Growth

Traditionally, systemic treatment for high stage colorectal carcinoma (CRC) is mainly fluorouracil-based chemotherapy [1]. The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, by acting on specific molecular pathways in tumor growth or modulating immune response towards tumor cells, provide a more targeted response, a better side effect profile and greater impact on patient survival compared with conventional molecules. This monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor, is known to be effective only in a subset of KRAS wild-type colorectal cancers. Patients with mutations in either KRAS or NRAS gene are not eligible for anti-EGFR monoclonal antibody therapy [3]. This is due to downstream activation of the Ras/Raf/MAPK pathway by mutated RAS protein, leading to cell proliferation which cannot be sufficiently inhibited by anti-EGFR receptor monoclonal antibodies [4]. With the increasing choices of targeted agents, more and more biomarkers are tested. Currently, the standard recommended biomarker panel for colorectal carcinoma would include KRAS, NRAS, BRAF gene hotspot mutation detection and microsatellite instability test [5]. With the advances in genomic profiling and sequencing and the understanding of the resistance mechanisms, the contraindication of anti-EGFR therapy in mutant KRAS patients may be revised. Based on the fact that the KRAS mutation in CRC suppresses the phosphorylation of the AMP-activated protein kinase (AMPK) known to be toxic for the tumor cells, Hua et al obtained a satisfactory response to for the anti-EGFR antibodies in mutant KRAS CRC xenograft models after reactivation of the AMPK [6]. Knickelbein et al demonstrated that the anti-EGFR antibodies induce the death of CRC cells via a p73- dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein (PUMA). This action is abolished in case of KRAS mutation. These authors admitted that the restoration of this pathway by inhibiting aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies [7]. In fifty-one CRC patient-derived xenografts study, Lee et al showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. The use of an anti-EGFR IgG1 antibody that displays potent inhibitory effects on highaffinity EGFR ligand enhanced CRC KRAS mutant cells cytotoxicity [8]. Dealing with the resistance to targeted therapies in CRC patient looks feasible. It could allow to broaden the indications of anti-EGFR therapy and provide a better survival for a larger group of CRC patients. In this era of precision and personalized medicine, a complete case specific tumor profiling and the comprehensive study of the tumorogenesis mechanisms should allow to overcome the intrinsic and acquired resistance to these targeted high effective therapies.

scholarly journals Generation and Characterization of Rat Monoclonal Antibodies Against Epidermal Growth Factor Receptor

2015 ◽  
Vol 34 (6) ◽  
pp. 418-422 ◽  
Author(s):  
Tomohiro Osaki ◽  
Cai-Xia Wang ◽  
Taro Tachibana ◽  
Masayuki Azuma ◽  
Masaya Kitamura ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP

1992 ◽  
Vol 12 (12) ◽  
pp. 5816-5823
Author(s):  
D Park ◽  
S G Rhee
Keyword(s):  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Immunoglobulin M ◽  
Rat Tissues ◽  
A431 Cells ◽  
Sh3 Domains ◽  
Epidermal Growth ◽  
Stimulation Of

The 47-kDa protein coimmunoprecipitated with phospholipase C (PLC)-gamma 1 by anti-PLC-gamma 1 monoclonal antibodies is proved to be Nck, a protein composed almost exclusively of one SH2 and three SH3 domains. Nck and PLC-gamma 1 are recognized by certain anti-PLC-gamma 1 monoclonal antibodies because Nck and PLC-gamma 1 share an epitope that likely is located in their SH3 domains. Nck is widely distributed in rat tissues, with an especially high level of expression in testes. The expression levels of Nck remains unchanged during the development of rat brain, whereas PLC-gamma 1 decreases during the same developmental period. Stimulation of A431 cells with epidermal growth factor elicits the tight association of Nck with the epidermal growth factor receptor and phosphorylation of Nck on both serine and tyrosine residues. The phosphorylation of Nck is also enhanced in response to stimulation of the nerve growth factor receptor in PC12 cells, the T-cell receptor complex in Jurkat cells, the membrane immunoglobulin M in Daudi cells, and the low-affinity immunoglobulin G receptor (Fc gamma RII) in U937 cells. The phosphorylation of Nck was also enhanced following treatment of A431 cells with phorbol 12-myristate 13-acetate or forskolin. These results suggest that Nck is a target for a variety of protein kinases that might modulate the postulated role of Nck as an adaptor for the physical and functional coordination of signalling proteins.

scholarly journals Chemotherapy versus erlotinib as second-line treatment in patients with advanced non-small cell lung cancer and wild-type epidermal growth factor receptor: an individual patient data (IPD) analysis

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000327
Author(s):  
Marina Chiara Garassino ◽  
Tomoya Kawaguchi ◽  
Vanesa Gregorc ◽  
Eliana Rulli ◽  
Masahiko Ando ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Individual Patient Data ◽  
Growth Factor Receptor ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
Mean Survival Time ◽  
Epidermal Growth

The efficacy of second-line treatment in patients with epidermal growth factor receptor (EGFR) wild-type tumours is still debatable. We assessed the efficacy of a standard second-line chemotherapy compared with erlotinib in an individual patient data approach for meta-analysis. The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS). Both were compared by log-rank test. The ‘restricted mean survival time’ (RMST) was estimated in each study and the difference in mean survival time up to the last available time point was calculated. The Cox proportional hazards model was used on survival analyses to provide HRs, to adjust for confounding variables and to test possible interaction with selected factors. Three randomised trials comparing chemotherapy versus erlotinib were analysed, including 587 randomised patients. Overall, 74% of patients included in the original trials were considered. 464 deaths and 570 progressions or deaths were observed. Compared with erlotinib, chemotherapy was associated to a decreased risk of progression (29%; HR: 0.71, 95% CI: 0.60 to 0.84, p< 0.0001;) but with no statistical significant reduction in OS (HR: 0.89, 95% CI: 0.74 to 1.06; p<0.20). No heterogeneity was found in both analyses. Patients treated with chemotherapy gained an absolute 1.5 and 1.6 months, respectively, in PFS and lifetime (RMST 95% CI: PFS 0.49 to 2.44; OS 95% CI: −1.04 to 4.25). These results showed that patients without a constitutively activated EGFR had better PFS with chemotherapy rather than with erlotinib while no statistical difference was observed in OS.

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