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.

The EVA-PCD™ Platform

At the recent meeting of the American Association for Cancer Research (AACR) held in Washington D.C (April 16-21, 2010), the theme remained consistent with the ground swell of interest in personalized care. Many of the sessions reflected the changing paradigm of clinical trials with a growing focus on biomarker analysis and patient selection predicated on genomic and proteomic features. Among the most compelling presentations were those that examined the manifest complexities of human signaling circuits. One presentation by Dr. Neal Rosen from Memorial Sloan Kettering in New York examined redundancy and feedback as principal determinants of clinical response to signal inhibitors. That session, chaired by Dr. Engleman from Harvard Medical School, examined the cross talk between EGFr and PI3K pathways. Using cell line systems, these investigators drilled down onto RNA and DNA expression profiles to examine how inhibitors acting for one pathway might up or down regulate parallel pathways.

This work dovetailed perfectly with our presentation on Monday, April 19, 2010 (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, proceedings AACR 2010). In this analysis, we used small molecules tyrosine and serine/threonine kinase inhibitors to examine the points of commonality and disparity in these two crucial signaling pathways to assess how future drug combinations might provide response with these novel classes of agents.

The most exciting aspect of our work is the capacity of the human tumor micro-spheroid platform (EVA-PCD™) to capture all of the operative mechanisms of response and resistance. This, more closely than other platforms, recapitulates the complexity of human tumors and provides insight into these  complex and redundant biological pathways. No genomic or proteomic tool can approximate the clinical relevance of the EVA-PCD™ platforms’ predictions.