Pharmacogenetics of small-molecule tyrosine kinase inhibitors: Optimizing the magic bullet

Cancer treatment has undergone revolutionary changes during the past decade, as a result of the introduction of tyrosine kinase inhibitors (TKIs) that selectively inhibit growth factor pathways critical for tumor growth. Unexpected toxicity profiles and disappointing response rates to these 'magic bullets' have prompted research to identify markers that can predict toxicity or response to such agents. This review discusses the results of pharmacogenetic studies that have used germline DNA to assess the effects of various polymorphisms on currently available small-molecule TKIs. In these studies, polymorphisms in the EGFR gene (ie, EGFR CA-repeat and -216G > T) have consistently been associated with response to the EGFR-blocking TKIs gefitinib and, to a lesser extent, erlotinib. In addition, results from studies investigating polymorphisms in drug transporting enzymes ( ie, ABCB1 1236T > C, 2677G > T/A and 3435C > T, and ABCG2 421C > A) suggest such polymorphisms are relevant for the pharmacokinetics of the TKIs; however, some conflicting findings on these polymorphisms have been published. The clinical impact of polymorphisms in EGFR and in drug transporting enzymes needs to be evaluated and validated in order for these pharmacogenetic markers to be applied successfully to individualize treatment in the clinic.Experimentele farmacotherapi

Pharmacogenetics of small-molecule tyrosine kinase inhibitors: Optimizing the magic bullet

Cancer treatment has undergone revolutionary changes during the past decade, as a result of the introduction of tyrosine kinase inhibitors (TKIs) that selectively inhibit growth factor pathways critical for tumor growth. Unexpected toxicity profiles and disappointing response rates to these 'magic bullets' have prompted research to identify markers that can predict toxicity or response to such agents. This review discusses the results of pharmacogenetic studies that have used germline DNA to assess the effects of various polymorphisms on currently available small-molecule TKIs. In these studies, polymorphisms in the EGFR gene (ie, EGFR CA-repeat and -216G > T) have consistently been associated with response to the EGFR-blocking TKIs gefitinib and, to a lesser extent, erlotinib. In addition, results from studies investigating polymorphisms in drug transporting enzymes ( ie, ABCB1 1236T > C, 2677G > T/A and 3435C > T, and ABCG2 421C > A) suggest such polymorphisms are relevant for the pharmacokinetics of the TKIs; however, some conflicting findings on these polymorphisms have been published. The clinical impact of polymorphisms in EGFR and in drug transporting enzymes needs to be evaluated and validated in order for these pharmacogenetic markers to be applied successfully to individualize treatment in the clinic

Pharmacogenetics of tomorrow: the 1+1=3 principle

Disappointing results from replicating pharmacogenetic association studies have prompted the search for novel statistical techniques to analyze the data, while taking into account the biological complexity underlying drug response. Two of these techniques multifactor dimensionality reduction and classification and regression tree analysis will probably be applied in increasing numbers of future pharmacogenetic studies. In this article, we describe the concepts underlying both techniques and illustrate their application in a recent pharmacogenetic study.Personalised Therapeutic

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer.

Contains fulltext : 87633.pdf (publisher's version ) (Closed access)BACKGROUND: Next to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients. METHODS: Germline DNA was isolated from 246 KRAS wild-type mCRC patients who were treated in the phase III CAIRO2 study with chemotherapy and bevacizumab alone or with the addition of cetuximab. Associations of epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) CA(14-22), cyclin D1 (CCND1) 932G>A, fragment-C gamma receptor (FCGR) 2A 535A>G and FCGR3A 818A>C polymorphisms with progression-free survival (PFS) and cetuximab-related skin toxicity were studied. RESULTS: In cetuximab-treated patients, the FCGR3A 818C-allele was associated with decreased PFS compared with the FCGR3A 818AA genotype (median PFS, 8.2 [95%CI, 6.7-10.3] versus 12.8 [95%CI, 10.3-14.7] months, respectively; HR, 1.57 [95%CI, 1.06-2.34]; P=.025). The EGFR20 genotype was associated with decreased PFS compared with the EGFR<20 genotype (median PFS, 7.6 [95%CI, 6.7-10.0] versus 12.4 [95%CI, 10.3-13.4] months, respectively; HR, 1.58 [95%CI, 1.06-2.35]; P=.024). The FCGR3A and EGFR polymorphisms were not associated with PFS in patients treated without cetuximab. None of the polymorphisms were associated with the incidence of grades 2-3 skin toxicity. CONCLUSION: EGFR and FCGR3A germline polymorphisms are associated with PFS in KRAS wild-type mCRC patients treated with cetuximab, bevacizumab and chemotherapy.1 juli 201

Activation of Tumor-Promoting Type 2 Macrophages by EGFR-Targeting Antibody Cetuximab

Purpose: In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high-affinity Fc gamma RIIIA. Experimental Design: The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the Fc gamma RIIIA polymorphism (CD16). Results: Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (Fc gamma R) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, Fc gamma Rs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers. Conclusion: These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies. ClinCancer Res; 17(17); 566873. (C)2011 AACR

Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) are located 900 kb proximal to the DFN3 gene POU3F4.

Item does not contain fulltex