Preclinical studies exploring a combination of anti c MET therapeutic agents with mTOR inhibitors have also demonstrated increased growth suppression compared with mTOR inhibitors alone. Chemotherapy remains the mainstay of treatment for several malignancies, even though advances in the molecular knowledge of cancer continue to support the development of selective targeted compounds. However, the use of conventional GS-1101 chemotherapy is often limited by de novo or acquired resistance, typically resulting from increased growth factor receptor signaling. These observations have prompted growth factor receptor inhibitors to be evaluated in combination with chemotherapy. Successful clinically validated examples of this approach include cetuximab, an anti EGFR antibody, in colorectal cancer and trastuzumab in patients with ERBB2 amplified breast cancer. Emerging preclinical data suggest that inhibitors of the HGF/c MET signaling pathway may also be effective in combination with chemotherapy.
The Pharmacologic Audit Trail Pharmacodynamic and pharmacokinetic data together allow the construction of a framework, known as the,pharmacologic audit trail,, for rational decision making in clinical trials. The PhAT allows all the key stages in drug development to be linked and interpreted Cytisine in relation to measured parameters and provides a stepwise,audit, to assess the risk of failure during the development of a novel compound at any particular stage. An updated PhAT has recently been developed to reflect the evolving drug discovery and development landscape, implementing the evaluation of potential predictive assays earlier in the drug development process and strategies to reverse resistance mechanisms .
This updated version recommends inclusion of the identification and initial clinical qualification of robust predictive biomarker assays for patient selection early in the drug development process. The inclusion of intermediate endpoint biomarkers, which should be identified and studied in the audit trail as early predictors of antitumor activity, is also recommended. Because there is an ongoing need to acquire more data from preclinical models on the relationship of anticancer drug antitumor activity and the required degree and duration of target blockade, careful assessment is warranted as to whether this is safely achievable in clinical trials and the PhAT should be seen as a useful tool. Conclusions Optimal methods for the assessment of HGF/ c MET overexpression or MET amplification have yet to be determined.
Traditional histopathological diagnosis remains important when evaluating the extent of phenotypic aggressiveness, but personalized molecular diagnosis is needed to understand whether a tumor in one specific patient carries a particular genetic alteration that could be targeted by a particular therapy. In the case of c MET, the current challenge is to identify the genetically defined responsive patient subsets that could benefit from c MET inhibition and therefore enable appropriate patient selection strategies to be implemented in future clinical studies. This calls for a vast preclinical strategy of tumor categorization based on genetic makeup, responsiveness to c MET inhibition and follow up validation of surrogate indicators of c MET activity. Treatment selection should be driven by a detailed understanding of the genetics and biology of the patient and their cancer.