Research Projects / Future Directions

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Quantitative approaches for studying patients in clinical trials

In cancer, response to targeted inhibitors is determined not only be the presence of the key mutant targets, but also by other critical changes in the molecular circuitry of cancer cells; e.g. such as loss of key tumor suppressor proteins, the selection for kinase resistant mutants and the deregulation of feedback loops. Understanding these networks and developing ways to identify and study them in patients is critical for developing rational combination therapies to suppress resistance. Traditional pathological examination, the "gold standard" of cancer diagnostics, may not be well-suited towards molecularly targeted approaches because it makes lineage type distinctions based on morphology that do not reveal the underlying molecular networks that determine response to signal transduction inhibitors. We have begun to develop new quantitative tools for measuring signaling networks in patients treated in state of the art clinical trials and have applied them towards identifying molecular determinants of response, and resistance to targeted therapies (Mellinghoff et al., NEJM, 2005; Yoshimoto et al., Clin. Cancer Res., 2008; Cloughesy et al., PLoS Med., 2008).

Through our collaborations with the Heath laboratory at CalTech (www.its.caltech.edu/~heathgrp/) in work supported in part by our NanoTechnology Center of Excellence (http://www.caltechcancer.org/) and through the Ben and Catherine Ivy Foundation (http://www.ivyfoundation.org/), we are developing a suite of new technologies for the measurement of key signaling molecules from defined populations of cells, tumor cells, immune cells, and support cells, directly from clinical tumor samples, and from the blood of patients. These (and other) measurements are making it abundantly clear that the heterotypic microenvironment that characterizes the interactions between different types of cancer cells (i.e. stem cells and non-stem cells), between cancer cells and immune cells and support cells may be critical for determining response to targeted agents. The Mischel laboratory aims to capture both the evolving communication networks between these cell types, and the relationship between those networks and the evolving physical environment, in order to develop or more effectively utilize targeted therapies.