Editorial

Although cytotoxic chemotherapy is still the cornerstone of systemic therapy for cancer, these treatments have marginal effectiveness in many malignancies and cause significant toxicity. It is now almost 20 years ago that the epidermal growth factor receptor (EGFR) was first proposed as a potential target for cancer. The EGFR TKI's gefitinib and erlotinib have shown activity in NSCLC while cetuximab is an active agent in metastatic colorectal cancer. However, several pivotal trials of these new agents have failed to give the expected improved results. One possible reason given for the failure of the phase 3 trials combining EGFR inhibitors with doublet chemotherapy for first-line treatment of advanced NSCLC was the lack of patient selection with regard to tumor sensitivity to EGFR inhibition. The most obvious marker of sensitivity to these agents is the EGFR expression level in a tumor. However, it has been demonstrated that the presence of this receptor alone does not predict response to either gefitinib or erlotinib in NSCLC. Other factors such as activation of EGFR in a particular patient may be critical determinants of response. The knowledge that some tumors have driving target aberrations coupled with gene-sequencing data provides the means to establish proof of principle about the validity of targets and/or targeted therapeutics. A second lesson was learned in the failure of therapeutic efforts directed at Ras. Ras is situated at the apex of the MAPK pathway and belongs to a superfamily of guanine nucleotide triphosphates (GTPases) that transmit proliferative and survival signals. Ras plays a central role in an intricate array of signal transduction pathways characterized by crosstalk, feedback loops, and multicomponent signaling complexes. One strategy to overcome the challenges inherent in developing therapeutics against signaling elements situated in redundant pathways is to target elements downstream of convergence points of critical signaling modules. This reasoning has led to interest in Raf kinase, which is one of several downstream effectors of Ras, as target for therapeutic development against cancer. Promising small molecule inhibitors of Raf kinase include sorafenib (BAY43-9006) and sutent (Pfizer SU) in renal cell cancer. Given that multiple pathways are often implicated in tumor cell growth, and the high likelihood for crosstalk between the components of these pathways, single targeted agent inhibitior therapy may be insufficient to induce durable antitumor effects. Targeted agents may be combined to allow vertical or horizontal inhibition of relevant pathways. Vertical inhibition targets multiple points within the same molecular pathway, whereas horizontal inhibition acts at points across multiple pathways. The efficacy of horizontal inhibition in advanced renal cell cancer is suggested by promising initial results combining the anti- EGFR agent erlotinib, with the anti-VEGF antibody bevacizumab. Finally, assessing antitumor activity with the new targeted drugs has also been challenging. In preclinical models, many targeted agents induce growth arrest or inhibition rather than tumor shrinkage. The 30% unidimensional shrinkage by standard Response Evaluation Criteria (RECIST) is an arbitrary standard that does not necessarily have biological or clinical significance. Indeed, both sorafenib and sutent are very active single agents in metastatic renal cell cancer when assessed by time to disease progression and not by RECIST criteria. The oncology literature is increasingly dominated by new biological targets and trials of targeted agents. In this issue of Current Cancer Therapy Reviews, the article by Luh and Alaui-Jamali reviews new targets, agents and drug resistance. The papers by Bader, Frank and Khan et al. discuss new potential targets such as YB-1, STAT-1 and survivin. The challenge to the medical oncologist is to assimilate this rapid growth of basic science information into successful clinical trials.