Aberrant signaling events play a central role in cancer and other diseases. Elucidating the architecture of signaling networks is therefore essential for understanding both normal and malignant growth. Because signaling processes involve many interacting components that act in concert for functionally-relevant collective phenomena to emerge, it is often difficult to intuit mechanistic principles from experimental observations. Further confounding intuition is the inherently stochastic character of the pertinent processes. Recent studies of primary cells and well-characterized cell lines provide vivid examples of such complexity and heterogeneity of biological signaling networks. Our recent studies also illustrate how complementary theoretical and experimental studies can help elucidate complex features of Ras signaling in lymphocytes. The central theme of this project is to employ such an approach at the crossroads of the physical and life sciences to deconvolute the origins of aberrant Ras signaling and its consequences in the context of a specific T cell lymphoma observed in the clinic. We ex pect our findings to have broad implications for diverse cancers. This goal will be achieved by pursuing the following specific aims:
(Aim 1) To extend computational models of receptorinduced Ras activation in normal T lymphocytes to include the downstream RAF/MEK/ERK-.PISkinase/Akt/mTOR/S6klnase-, and RalGDS-effector pathways, and cross-talk between these pathways. Model predictions will be used to design experiments that can discriminate sensitively between different hypotheses. We will then iterate between experiments and computational studies.
(Aim 2) To develop the models further by testing computational predictions against normal and oncogenic Ras mutant as well as oncogenic RasGRPI T cell lymphoma models. The paradigm of iteration between computational and experimental studies will be followed. Analyze the effects of complex cooperating genetic lesions.
(Aim 3) To use computational models to define critical oncogenic nodes within the networks and test the predicted lymphoma's vulnerability experimentally via chemical inhibitors, shRNA, and novel Kras alleles that are defective for PI3 kinase or RAF activation.
Aberrant Ras signaling is a fundamental molecular lesion in many human cancers, but Ras proteins are widely regarded as undruggable. For this reason, attention has turned toward developing agents that target downstream kinase cascades such as Ral- GDS, Raf/MEK/ERK, and PI3 kinas/Akt/mTOR. Recent studies in our laboratories and by other groups have uncovered unexpected complexity and heterogeneity in these downstream signaling networks. Our goal is to bring together computational techniques from physical sciences with cancer biology to understand normal Ras-regulated signaling networks and characterize how these networks are remodeled and modulated in cancer. Our studies using T cell leukemia/lymphoma as a model for cancer in general should provide a framework for future preclinical and clinical trials aimed at improving survival while minimizing therapy-related toxicities.
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