2012 Program Booklet - MCD Biology - University of Colorado Boulder

Michael B. Yaffe, PhD
Professor, Department of Biology
Massachusetts Institute of Technology (MIT)
Title: Systems Biology Approaches to
Optimizing Cancer Treatment
Saturday, October 13
9:20 – 10:15 am
JSCBB Butcher Auditorium
Abstract:
Most current anti-­‐cancer drugs function by one of two general mechanisms: (1) targeting specific signaling
molecules, particularly protein kinases and growth factor receptors; and (2) inducing cytotoxicity through DNA
damage or disruption of the mitotic spindle. Targeted agents/signaling inhibitors, when used as
monotherapies for cancer treatment are non-­‐curative. Although these drugs can induce dramatic tumor
regression, and occasionally prolonged remissions, the cancers invariably recur. Alternatively, cytotoxic
therapies that damage DNA have a long history of successful use as anti-­‐neoplastic agents. However, patient
responses to DNA damaging drugs vary greatly, and heterogeneity within any single tumor can lead to the
emergence of a resistant sub-­‐population of cells. The DNA damage from exposure of tumor cells to these
cytotoxic agents is processed by a complex interacting network of signaling pathways involving protein
kinases, phosphoserine/ threonine-­‐binding domains (14-­‐3-­‐3 proteins, FHA domains, BRCT domains), and
ubiquitin/SUMO modifying enzymes. The outputs of these DNA damage-­‐activated pathways must be
integrated with additional extracellular and intracellular cues such as cytokines and growth factor signals to
control the resulting cellular response – cell cycle arrest, DNA repair, apoptosis or senescence. How this array
of diverse signals is functionally integrated and processed, and how these signal integration events can be
influenced by combinations of anti-­‐cancer therapies to enhance tumor cell killing is unknown.
To address this, we have been developing systems biology-­‐based models of DNA damage signaling
where gene expression signatures, kinase activities, protein phosphorylation, and phosphoprotein-­‐binding
events for multiple signaling pathways are quantitatively measured at densely sampled points in time, along
with cellular responses such as cell cycle arrest, autophagy, and apoptosis. The resulting large dataset of
signals and responses are then related to each other mathematically using partial least squares regression,
principal components analysis, and time-­‐interval stepwise regression. We have used this approach to examine
the response of breast cancer and osteosarcoma cells to DNA damaging chemotherapy and gamma radiation
in the presence or absence of small molecule inhibitors of growth factor signaling pathways. The resulting
models, built from thousands of signaling measurements and hundreds of cellular response assays, reveals
surprisingly paradoxical context-­‐dependent roles for the MEK-­‐Erk and p38/MK2 kinase signaling pathways in
controlling cell cycle arrest, apoptosis and senescence after DNA damage. Using this approach, we recently
identified a novel time-­‐staggered combination therapy in which EGFR inhibitor pre-­‐treatment is used to
dramatically enhance DNA damage-­‐induced cell death in a subset of triple-­‐negative breast cancers by dynamic
re-­‐wiring of apoptosis pathways. The results from these systems-­‐based studies illustrate the importance of
measuring time-­‐dependent changes in signaling pathways in evaluating and optimizing the effects of anti-­‐
cancer drugs, and show the utility of a new concept – therapeutic network re-­‐wiring – in designing novel
combination therapies with greater anti-­‐tumor efficacy.