Understanding the basis for resistance to molecular targeted therapies is hindered by our inability to infer the functional circuitry of the signaling network that is perturbed by a molecular targeted drug within a heterogeneous population of cancer cells. Thus, there is an urgent need to create the intellectual foundation for prognostic tools to infer how cancer cells interpret biochemical cues present in the tumor microenvironment. Our long-term goal is to improve the clinical outcomes for cancer by designing novel treatments to surmount de novo and acquired resistance to molecularly targeted therapies. Thus, the proposed research is relevant to NIH's mission by developing fundamental knowledge that will potentially help to reduce the burdens of human cancer. The overall objective of this application is to validate a prediction that alterations in protein expression among elements of a signaling network redirect the flow of information down novel branches of a signaling network. Our central hypothesis is that the reported variation in protein expression among breast cancer cells alters the flow of intracellular information among branches of a signaling network that alters gene expression (i.e., the functional topology). We plan to test our central hypothesis and accomplish the overall objective of this application by pursuing the following specific aim: 1) Establish that the functional topology of signaling networks depends on differences in protein expression. Our approach will be to test the hypothesis using a series of synthetic signaling models, created using epitope-tagged proteins that function as network nodes and vary in their expression. We will assess whether the extent of protein-protein interaction varies with basal protein expression level and whether a new branch imparts new functionality to the signaling network. The rationale that underlies the proposed research is that identifying how changes in expression of signaling proteins alter a cell's signaling network may lead to an improved understanding of resistance to molecular targeted therapies and to improved management of breast cancer patients. This proposed research is projected to yield the following expected outcomes. First, this project will validate a computational framework for interpreting how expression patterns of signaling proteins modulate cellular response to molecular targeted cancer drugs. Creating new technologies to facilitate comprehensive study of biological pathways is a NIH Roadmap Initiative. Second, the proposed research will promote a multi-disciplinary research environment at the interface between model-based inference, cancer biology, proteomics, and molecular biology - an example of a research team of the future and a NIH Roadmap Initiative. The expected outcomes will have an important positive impact because they focus creating the knowledge and expertise necessary for developing the predictive tools of personalized medicine to improve the clinical management of cancer with an initial emphasis on breast cancer.

Public Health Relevance

The proposed multi-disciplinary studies are an important step towards understanding how alterations in how cancer cells process information may influence clinical response to trastuzumab in breast cancer patients. The proposed research is expected to have an important positive impact on public health, because the approach proposed will enable improved therapies that surmount de novo and acquired resistance to trastuzumab in breast cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Academic Research Enhancement Awards (AREA) (R15)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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West Virginia University
Engineering (All Types)
Schools of Engineering
United States
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Wang, Qing; Klinke 2nd, David J; Wang, Zhijun (2015) CD8(+) T cell response to adenovirus vaccination and subsequent suppression of tumor growth: modeling, simulation and analysis. BMC Syst Biol 9:27
Klinke 2nd, David J (2015) Enhancing the discovery and development of immunotherapies for cancer using quantitative and systems pharmacology: Interleukin-12 as a case study. J Immunother Cancer 3:27
Wu, Yueting; Deng, Wentao; Klinke 2nd, David J (2015) Exosomes: improved methods to characterize their morphology, RNA content, and surface protein biomarkers. Analyst 140:6631-42
Klinke 2nd, David J; Horvath, Nicholas; Cuppett, Vanessa et al. (2015) Interlocked positive and negative feedback network motifs regulate ?-catenin activity in the adherens junction pathway. Mol Biol Cell 26:4135-48
Klinke 2nd, David J; Birtwistle, Marc R (2015) In silico model-based inference: an emerging approach for inverse problems in engineering better medicines. Curr Opin Chem Eng 10:14-24
Klinke 2nd, David J (2014) In silico model-based inference: a contemporary approach for hypothesis testing in network biology. Biotechnol Prog 30:1247-61
Klinke 2nd, David J; Kulkarni, Yogesh M; Wu, Yueting et al. (2014) Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models. Biotechnol Bioeng 111:1853-63
Klinke 2nd, David J (2014) Induction of Wnt-inducible signaling protein-1 correlates with invasive breast cancer oncogenesis and reduced type 1 cell-mediated cytotoxic immunity: a retrospective study. PLoS Comput Biol 10:e1003409
Kulkarni, Yogesh M; Liu, Changxing; Qi, Qi et al. (2013) Differential proteomic analysis of caveolin-1 KO cells reveals Sh2b3 and Clec12b as novel interaction partners of caveolin-1 and Capns1 as a potential mediator of caveolin-1-induced apoptosis. Analyst 138:6986-96
Klinke 2nd, David J; Finley, Stacey D (2012) Timescale analysis of rule-based biochemical reaction networks. Biotechnol Prog 28:33-44

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