Highly Productive Targeted Therapies

The introduction of targeted therapies now provides select patients the opportunity to receive first-line therapies with these new classes of drugs. The recognition that epidermal growth factor tyrosine kinase inhibitors are most effective in patients with EGFr mutations (codons 19-21) has enabled us to apply the EGFr mutation analysis as a biomarker for response. Despite the high response rates (up to 70% in mutation positive patients), approximately 30% of patients with the appropriate biomarker do not respond. In addition, patients who do not carry EGFr mutations can nonetheless respond to these classes of drugs. This reflects the complexity, redundancy and promiscuity of signal pathways, such that, pathway cross talk has the capacity to salvage cancer cells from the lethal effects of these inhibitors. The EVA-PCD™ platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death. Our earliest work, gefitinib conducted in 2001, identified non-small lung cancer as an important target disease. As we continued this work with gefitinib (Iressa) and erlotinib (Tarceva), we have had the opportunity (under IRB-approved protocol) to treat patients with first line Tarceva. To date, we are tracking a 100% response rate to Tarceva in the select populations; even patients who have not been found to carry recognized mutations. More interesting, patients not expected to respond such as one multiply recurrent male, smoker has remained in a 4 year remission on Tarceva as a third line therapy. As predicted by EVA/PCD analysis, the emerging study of combined signal inhibitors provides the opportunity to examine favorable combinations for effect and synergy. The rational combination of signal inhibitors is a highly productive avenue of research under investigations in many centers, including our laboratory. Consistent with our presentation at the recent meeting at the American Association for Cancer Research (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, proceedings AACR 2010), the dual inhibition of the PI3k and EGFr pathways may prove highly productive. This work is ongoing at our center.