Advances in cancer therapy increasingly reflect the application of genomics and proteomics to target tumor-specific phenomena. Several insights have accelerated this process including the primacy cell survival signals in carcinogenesis and drug resistance and the growing appreciation of tumor biology as contextual. Ex vivo analysis of programmed cell death (EVA/PCD™) addresses both issues by measuring metabolic and morphologic features of drug induced cell death (apoptotic and non-apoptotic) using native state 1° cultures isolated from surgical specimens and cytologically (+) fluids. The predictive validity of the EVA/PCD™ established for cytotoxics, e.g,. 2CDA in hairy cell leukemia; purine-alkylator synergy in NHL (Nagourney et al, B.J. Cancer, ‘93) and platin-gemcitabine activity/synergy in breast and gynecologic cancers (Nagourney et al, Deoxynucleoside analogs in cancer therapy, Humana Press, 2006) has led to this platforms current focus on signal transduction with a growing emphasis on NSCLC. A recent report in NSCLC provided an ORR of 62%, med TTP of 9.5 mos and med OS of 22.3 mos, including the identification of durable responders to EGFr-TKIs (Nagourney RA Proc ASCO, 2010). An EVA/PCD™ exploration of “vertical” and “horizontal” signal inhibition (Nagourney et al Proc AACR, 2010) favored “horizontal” strategies in NSCLC providing very durable clinical responses with dual EGFr/VEGFr and clinical response for dual EGFr/mTOR salvage following single agent EGFr-TKI failure. By expanding beyond current FDA-approved drugs into the new agents that target PI3K, AKT, TORC1&2, MEK/ERK and c-MET, the EVA/PCD™ can facilitate developmental therapeutics. Analyses are now examining the activity and synergy of EGFr-TKIs with VEGF, mTOR, MEK/ERK, PI3K, AKT and c-MET inhibitors in NSCLC and other diseases as will be reported. Supported in part by a research grant from Biophysica, Ltd, the Vanguard Cancer Foundation and The Nagourney Institute.
Fourth AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development– Sep 27-30, 2010; Denver, CO