Conquering the challenges of genotypic and phenotypic tumor heterogeneity to realize the promise of personalized cancer therapy: the role of academia.

The advent of rapid and progressively more affordable sequencing and gene expression studies have spurred research on therapies for cancer targeted to specific gene alterations. With few exceptions, such as those cancers with either a paucity of mutations or major chromosomal rearrangements driving the neoplastic transformation, the approaches based on one mutational target-one drug have achieved only modest outcomes in cancer. Using the paradigm of aggressive breast cancers, we will show the mathematical explanation that predicts our failures and indicates a plausible way forward. An integrated network modeling approach to intracellular signaling, metabolism, and microenvironment interactions, coupled with the use of synthetic devices engineered to understand phenotypic heterogeneity of cancer lesions, may form the basis for selection of the next-generation of personalized therapies for cancer. Academia can play a larger role in bringing effective drugs to first-in-human trials in this context.