Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo

Abstract

Molecular therapeutics, targeting the underlying defects leading to cancer initiation and progression, are the “holy grail” of cancer research, translation, and therapy. This quest has taken a major leap forward with the demonstration that STI571 (Gleevec) induces clinical remissions in over 90% and molecular remissions in 10–20% of patients with IFN-refractory chronic phase chronic myelogenous leukemia (CML). The efficacy of STI571 in CML has been shown to be caused by the requirement of the bcr/abl fusion protein, unique to CML, for its initiation and progression, requiring molecular diagnostics to identify sensitive patients. A plethora of molecular therapeutics targeting signal transduction pathways are under evaluation. Despite the presence of the target in normal cells, the drugs have, in general, been remarkably nontoxic as compared with conventional chemotherapy or radiation therapy (see Fig. 1). As expected, these agents exhibit little, if any, activity in tumors where the target is not amplified or activated. Thus individualization of therapy driven by effective molecular diagnostic approaches to determine the status of the targets in patients' cancers is as essential a component of a molecular therapeutics program as is the identification and validation of new targets or the development of novel targeted drugs. Normal cells have multiple functional signaling pathways. These signaling pathways exhibit a complex array of cross connections. When a specific signaling event is acutely inhibited, normal cells likely have multiple mechanisms available to bypass the effects of the blockade. Indeed, the lack of phenotype or modest phenotype in many knockout mice is compatible with this model. Alternatively, normal cells may be able to enter a resting state when specific signaling pathways are inhibited. In the addiction or genomic instability model, the genomic instability that is necessary for tumor initiation and progression may contribute to a loss of alternative signaling pathways. When a cell …