Review
Post ScreenPharmacogenetics of EGFR and VEGF inhibition
Post Screen
Section snippets
Epidermal growth factor (EGF) pathway
Cetuximab is a chimeric mouse/human IgG1-type MAb, whereas panitumumab is a fully human IgG2-type MAb. Both MAbs bind specifically to the extracellular domain of the EGFR and are competitive inhibitors of the natural ligands EGF and transforming growth factor-α (TGFα).
The small G protein k-ras, the protein kinase b-raf and phosphoinositide 3-kinase (encoded by KRAS, BRAF and PIK3CA, respectively) play a central role as intracellular mediators of EGFR signalling [5], ultimately leading to
Vascular endothelial growth factor (VEGF) pathway
Bevacizumab is a humanized IgG1-type MAb directed against soluble VEGF, one of the key moderators in angiogenesis, which is thought to be important for tumour growth and invasiveness [29]. VEGF exerts its pro-angiogenic effect via VEGF receptor-2, a tyrosine kinase receptor that is also referred to as kinase insert domain receptor (KDR). Transcription of VEGF is regulated by hypoxia inducible factor-1α (HIF1α) (Fig. 1).
Till date, five functional SNPs in the 5′ and 3′ regions of the VEGF gene
Polymorphisms for MAbs in general
The plasma half-life of MAbs is generally relatively long: the half-life of bevacizumab (20 days) is similar to that of endogenous IgG1, whereas the half-life of cetuximab and panitumumab is 70–100 hours and 7.5 days, respectively. The shorter half-life of the latter MAbs can in part be explained by internalization and degradation of the receptor–MAb complex after binding. It is postulated that antibodies of the IgG type, such as bevacizumab, are protected from degradation by the neonatal Fc
Copy number polymorphisms
An interesting novel field of pharmacogenetic research includes heritable variation of copy number of DNA segments of 1 kb or larger of the genome [58]. Analogous to the definition of a SNP, a CNP is a structural variant that occurs at a frequency of >1% in the population. Since the first whole genome array studies of this phenomenon were published in 2004 59, 60, an open-access online database has been developed in which structural variations of the human genome are assembled 60, 61 (see //projects.tcag.ca/variation
Discussion
It is accepted that germ-line polymorphisms (both SNPs and CNPs) have the potential to predict outcome of therapy. Predicting outcome of therapy with cetuximab, panitumumab and bevacizumab is especially warranted, as response rates are moderate, with possible serious adverse events, at high financial cost. In this review, we give an overview of studies on polymorphisms in candidate genes in the EGF and VEGF pathways.
Till date, only few small studies have shown an association of genetic
Glossary
- SNP (single nucleotide polymorphism)
- a change of a single base of germ-line DNA, as compared with wild-type, which occurs in ≥1% of the population. Because any individual carries two alleles, the SNP can be present in both alleles (homozygote), on only one allele (heterozygote) or not at all (wild-type).
- CNP (copy number polymorphism)
- in contrast to a SNP, a CNP encompasses ≥1000 base pairs or more. Regarding heritability and population frequency, the definitions are the same.
- Mutation
- a change in
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Cited by (48)
Single-nucleotide polymorphisms and haplotypes of vascular endothelial growth factor
2017, Gene ReportsCitation Excerpt :The 5′- and 3′-UTR contain key regulatory elements contributes to high variability in VEGF production among tissues (Schultz et al., 1999). It is likely that a small number of these polymorphisms and haplotypes actually have a functional effect on VEGF translation (Pander et al., 2007). VEGF polymorphisms have been associated with increased risks for several types of tumors (Jin et al., 2005; Sfar et al., 2006; Krippl et al., 2003; Kataoka et al., 2006), including lung cancer in Asian populations (Lee et al., 2005).
Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population
2016, Oral OncologyCitation Excerpt :Thirdly, cetuximab can induce antibody-dependent cell-mediated cytotoxicity (ADCC) [17] through the interaction of the Fc region of the monoclonal antibody with the Fc gamma receptor (FcgR) carried by macrophages and natural killer cells [18,19]. Clearly, clinical benefit and low toxicity with EGFR-targeting antibodies seems to be restricted to a particular subgroup of HNSCC patients [20]. Although critically required for managing the high cost of this type of therapy and their anticipated integration in other clinical regimens, no validated predictive factors are currently available to improve treatment decision making [20].
Oesophageal squamous cell carcinoma in high-risk Chinese populations: Possible role for vascular epithelial growth factor A
2014, European Journal of CancerComprehensive Immunomonitoring to Guide the Development of Immunotherapeutic Products for Cancer
2013, Cancer Immunotherapy: Immune Suppression and Tumor Growth: Second Edition