2012 Program Booklet - MCD Biology - University of Colorado Boulder

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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.
William S. Marshall, PhD President and Chief Executive Officer miRagen Therapeutics, Inc. Title: microRNA targeting as a novel approach to the development of cardiovascular therapeutics Saturday, October 13 10:35 – 11:20 am JSCBB Butcher Auditorium Abstract: Alterations in the expression of specific microRNAs have been observed in several cardiovascular disease models and human clinical samples, providing an exciting potential for therapeutic intervention. Genetic deletion studies that have been recapitulated by synthetic antimiR dosing studies demonstrated that the inhibition of certain microRNA’s is sufficient to produce beneficial outcomes in relevant disease models. Targeting such microRNAs with short, high-‐affinity oligonucleotides has demonstrated significant promise, as this strategy benefits from the altered biophysical properties of the antimiR compared to traditional antisense or RNAi gene targeting approaches. These characteristics contribute to enhanced pharmaceutical properties of the antimiR. An overview of our lead programs will highlight several key pharmacological observations that help build confidence in the lead molecules as they advance towards human clinical evaluation.
Page 1 and 2: 26 TH MCDB Graduate Student Symposi
Page 3 and 4: Past MCDB Graduate Student Symposia
Page 5 and 6: Keynote Speaker: William Freytag, P
Page 7: Keynote Speaker: Larry Gold, PhD Ch
Page 11 and 12: JoAnne Flynn, PhD Professor, Depart
Page 13 and 14: Jeffrey Settleman, PhD Senior Direc
Page 15 and 16: William Sullivan, PhD Professor, De
Page 17 and 18: Symposium Location Jennie Smoly Car
Page 19 and 20: 2012 PRESENTING SPONSORS Arts and S

2012 Program Booklet - MCD Biology - University of Colorado Boulder

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