Clinical experience of targeted therapies is at an early stage but it is likely that we will have an increasing number of treatment options available to us in the near future. (monotherapy or combination therapy regimens); and should we be giving them to? (acknowledging the need for patient selection). multiple targets The molecular-targeted brokers currently in development can be explained in terms of their target profile as being single- or multiple-target brokers (Table 1). However, the only brokers that are purely targeted against one receptor are the MAbs, as small molecule ATP-competitive brokers frequently have additional off-target activities against other Purvalanol B receptor tyrosine kinases, especially at higher doses. To date, our clinical experience is based on brokers with specific primary targets, that is, the anti-VEGF MAbs bevacizumab and cetuximab, and the EGFR TKIs erlotinib and gefitinib. A number of other highly selective brokers are in development, such as IMC-1C11, an anti-VEGFR-2 MAb and TKIs with VEGFR-specific activity (e.g. CEP-7055 and GW-786034), all of which have demonstrated promising efficacy and security in early clinical studies (Posey and c-Kit)?IMC-1121b (VEGFR-2 MAb)SU11248 (VEGFR-1, -2 and -3, Flt-3, PDGFR, c-Kit and CSF-1)?ZD6474 (VEGFR and EGFR)?AEE-788 (VEGFR, EGFR, erb)?AMG 706 (VEGFR, PDGFR, c-Kit and Ret) Open in a separate window Many of the newer brokers inhibit more than one receptor tyrosine kinase and these compounds may have unique inhibition profiles. For example, ZD6474 inhibits both VEGFR and EGFR tyrosine kinase activity, and therefore has the ability to block two key processes in tumour development (Wedge receptor and c-Kit (Solid wood activity against VEGFR-1, VEGFR-2, Flt-3, PDGFR, c-Kit and CSF-1 receptor tyrosine kinase activity (Abrams 18.8%), a longer median time to progression (7.4 4.2 months) and a trend towards increased survival (17.7 14.9 months) (Johnson 10.2 months with chemotherapy alone (unpublished data)?IIZD6474DocetaxelLocally advanced or metastatic NSCLC after failure of first- line platinum-based chemotherapy combined use of more selective agents. In particular, the tolerability issues associated with these methods will require careful evaluation in order to demonstrate whether it may be safer to use a combination of highly targeted brokers, or one multitargeted drug. Who? ? acknowledging the need for patient selection Heterogeneity is usually manifest at a number of levels in human malignancy; genetically, at the cellular level, zonally (within a tumour deposit), between tumour deposits, and between patients. An awareness and understanding of this heterogeneity is Rabbit Polyclonal to Cytochrome P450 2A6 key to the development of tailored biological therapies, and could be greatly assisted by the development of better, more predictive animal models. The goal of standard chemotherapies is usually to kill all rapidly proliferating cells, which accounts not only for its common application to all tumour types but also for its significant associated toxicity. Purvalanol B Targeted therapies, by definition, act in a far more specific manner, inhibiting biological pathways and processes that are selectively dysregulated in tumours, thereby avoiding many of the tolerability disadvantages of standard chemotherapy. As a result, however, it is likely that a one size fits all’ approach cannot be adopted with the novel brokers, and that a degree of patient selection may be required to identify the patients who are likely to benefit most from treatment. The successes and failures of clinical studies to date highlight the need to identify specific patient Purvalanol B types for treatment with the various targeted therapeutic approaches, and a great deal of additional investigation is required before we can claim to understand and optimise treatment. For example, despite the excellent data reported with bevacizumab plus chemotherapy in the first-line CRC study, investigation of this agent as a third-line therapy in combination with capecitabine in patients with metastatic breast cancer has shown evidence of activity (as seen by a significant increase in response rates), but no significant improvement in survival (Miller et al, 2005). Such evidence of biological activity that fails to translate into an overall survival benefit could be considered further evidence of the need for patient characterisation; it is likely that while specific approaches may be generally more effective in certain tumour types, subgroups of patients that demonstrate a survival benefit could be identified in a range of tumour types. Although the activity of antiangiogenic agents should theoretically apply to all solid tumours, there appear to be key differences between patient populations. One hypothesis is that although early-stage tumours may rely on VEGF as the principal proangiogenic factor, angiogenesis in.