Signal Transduction in Glioblastoma - the EGFR/PI3K pathway The Mischel laboratory aims to elucidate the signaling networks underlying sensitivity and resistance to kinase inhibitor therapy in glioblastoma patients and to use this information to develop molecularly targeted combination therapies. This strategy is tightly coupled to the development of new diagnostic approaches for rapid detection of relevant molecular signatures in clinical samples to facilitate the successful clinical translation of kinase inhibitor therapy. Achievement of these goals has the potential both to greatly improve clinical care for glioblastoma patients, and to shed light on the successful application of molecularly targeted therapies to patients with a variety of types of cancer. The EGFR/PI3K/Akt/mTOR signaling pathway is a major focus of our work (Mellinghoff et al., NEJM 2005; Choe et al., Cancer Res., 2003; Wang et al., Cancer Res., 2006; Horvath et al., PNAS 2006; Cloughesy et al., PLoS Med., 2008).
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.
Oncogenic signaling and cellular metabolism
Altered cellular metabolism is a hallmark of cancer. Cancer cells undergo a marked shift towards aerobic glycolysis ("the Warburg effect"), which reassigns ATP generation from the Krebs cycle to glycolysis and enables reprogramming of the mitochondria from energy production towards anabolic processes. This shift is essential to sustain the limitless proliferative capacity of cancer cells through de novo synthesis of nucleotides and lipids. The glycolytic phenotype of cancer permits non-invasive molecular imaging of many cancers, including glioblastoma, by Positron Emission Tomography (PET) using the glucose analog [18F]FDG. It also has a profound impact on tumor cell proliferation and survival through its effects on membrane biogenesis and modification of membrane proteins. The Mischel lab aims to elucidate the molecular circuitry linking oncogenic signaling with altered glioblastoma cellular metabolism in patients and model systems, and identify new molecularly targeted approaches based on disrupting this circuity. The Mischel laboratory has recently demonstrated a key role for AMPK in regulating the growth of EGFR-activated GBMs (Guo et al., PNAS, 2009). The Mischel laboratory has also recently found that inhibitors of fatty acid signaling promote apoptosis in glioblastoma cells with highly active EGFR signaling (Guo et al., Sci. Signaling, 2009).
The Mischel laboratory aims to elucidate the signaling networks underlying sensitivity and resistance to kinase inhibitor therapy in glioblastoma patients and to use this information to develop molecularly targeted combination therapies. This strategy is tightly coupled to the development of new diagnostic approaches for rapid detection of relevant molecular signatures in clinical samples to facilitate the successful clinical translation of kinase inhibitor therapy. Achievement of these goals has the potential both to greatly improve clinical care for glioblastoma patients, and to shed light on the successful application of molecularly targeted therapies to patients with a variety of types of cancer. The EGFR/PI3K/Akt/mTOR signaling pathway is a major focus of our work (Mellinghoff et al., NEJM 2005; Choe et al., Cancer Res., 2003; Wang et al., Cancer Res., 2006; Horvath et al., PNAS 2006; Cloughesy et al., PLoS Med., 2008).
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).