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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15CA132124-02
Application #
8232374
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2007-12-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$440,510
Indirect Cost
$142,868
Name
West Virginia University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
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) In silico model-based inference: a contemporary approach for hypothesis testing in network biology. Biotechnol Prog 30:1247-61
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
Klinke 2nd, David J; Finley, Stacey D (2012) Timescale analysis of rule-based biochemical reaction networks. Biotechnol Prog 28:33-44
Klinke 2nd, David J; Cheng, Ning; Chambers, Emily (2012) Quantifying crosstalk among interferon-ýý, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model. Sci Signal 5:ra32
Kulkarni, Yogesh M; Klinke 2nd, David J (2012) Protein-based identification of quantitative trait loci associated with malignant transformation in two HER2+ cellular models of breast cancer. Proteome Sci 10:11
Klinke 2nd, David J (2011) Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans. PLoS One 6:e26873
Finley, Stacey D; Gupta, Deepti; Cheng, Ning et al. (2011) Inferring relevant control mechanisms for interleukin-12 signaling in naive CD4+ T cells. Immunol Cell Biol 89:100-10
Klinke 2nd, David J (2010) Signal transduction networks in cancer: quantitative parameters influence network topology. Cancer Res 70:1773-82
Klinke 2nd, David J (2010) A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12. Mol Cancer 9:242

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