In one of these studies, cetuximab was reported to have superior activity in patients carrying FcRIIa-131H or FcRIIIa-158V alleles, a result that has previously been reported for other therapeutic antibodies

In one of these studies, cetuximab was reported to have superior activity in patients carrying FcRIIa-131H or FcRIIIa-158V alleles, a result that has previously been reported for other therapeutic antibodies.19Similar correlations for FcRIIa, but surprisingly different results with respect to FcRIIIa, were reported in a second study.20Since FcRIIa is predominantly expressed by myeloid effector cells, i.e., monocytes, polymorphonuclear leukocytes (PMN), and natural killer (NK) cells predominantly express FcRIIIa, these results may suggest that both NK cells and myeloid cells Rabbit Polyclonal to TEAD1 serve as effectors for EGF-R antibodies. inhibitors. == The epidermal growth factor receptor (EGF-R) belongs to the family of ErbB molecules, which constitute type I transmembrane tyrosine kinases. Upon binding GENZ-644282 of ligand, the receptor undergoes a conformational change from a tethered to an un-tethered configuration, which allows homo- or GENZ-644282 heterodimerization with other members of the family,1and leads to receptor activation and recruitment of downstream signaling molecules.2Transgenic expression of mutated EGF-R in mice induced tumors that resembled their human counterparts in many respects.3,4Overexpression or gene amplification of EGF-R is indeed found in many human tumor types.5Results such as these have underscored the importance of EGF-R to tumorigenesis, and have lead to wide-spread study of EGF-R inhibitors as anti-cancer agents. So far, two classes of EGF-R inhibitors have obtained regulatory approval for the treatment of cancer patients: orally available, small molecule tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs) (Tables 1and2).6Many other molecules, and also different approaches (e.g., immunotoxins, vaccination), are under clinical evaluation. To date, TKI have been particularly effective in non small-cell lung cancer (NSCLC), but ineffective in colorectal cancer (CRC). On the other hand, EGF-R antibodies are approved for treatment of CRC, as well as head and neck cancer, but evidence for efficacy in NSCLC is just emerging. Interestingly, several studies to combine TKI with cytotoxic chemotherapy failed, while the approved mAb therapeutic cetuximab is regularly combined with chemo- or radiotherapy. Here, we focus on EGF-R antibodies cetuximab and panitumumab as treatments for NSCLC and CRC. More detailed discussion about the clinical status of EGF-R inhibitors can be found in the literature.79 == Table 1. == EGF-R-directed antibodies in clinical development == Table 2. == Tyrosine kinase inhibitors targeting the EGF-R pathway RET, Rearranged during transfection; EPHB4, ephrin receptor B4. == Predictors of Response or Resistance to EGF-R-Directed Therapies == The concept of personalized medicine is based on the identification of patient-specific tumor characteristics that can be targeted by highly selective drugs.10Considering side effects and the high costs of these targeted therapies, the identification of markers that predict response or resistance to these novel reagents is crucial. Typically, prognostic and predictive markers are distinguished. According to this concept, prognostic markers should relate to intrinsic characteristics of the tumor and should be independent from specific therapy. In contrast, predictive markers are defined for a specific type of therapy, and may vary depending on the therapy under evaluation. In clinical practice, distinguishing these two types of markers may be difficult and identification and verification of predictive markers constitutes a considerable task.11 Although the need to identify biomarkers for EGF-R-directed therapy is GENZ-644282 widely acknowledged, there is considerable discord among studies regarding the suitability of individual markers (see below). Discrepancies between different studies may, in part, be explained by variations in assays and technologies, which make comparisons difficult. In the future, these problems may be overcome by standardization of biomarker.12 == Clinical Parameters == Clinical markers for response to tumor therapy typically include parameters like tumor stage and grading, histology, gender, ethnicity, co-morbidities and performance status. The impact of these parameters for conventional tumor therapy is well established. Analyses of early trials with EGF-R-directed TKI indicated that Asian origin, female gender, non-smoker status and adenocarcinoma/bronchoalveolar carcinoma (BAC) histology were strong predictors for response to these molecules in NSCLC.13Interestingly, selected patients with mutated EGF-R responded to gefitinib, even if they had a low performance status that rendered them poor candidates for conventional chemotherapy.14This latter observation suggested that GENZ-644282 conventional parameters for response prediction may not apply for targeted therapies. Both EGF-R-directed TKI and antibodies induce a typical acneiform skin rash, but several other skin reactions are also commonly observed. These dermatologic side effects negatively affect the quality of life of.