2014 — 2019 |
Gray, Joe W. Heiser, Laura Madeline Korkola, James |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Data Analysis @ Oregon Health & Science University |
0.912 |
2014 — 2019 |
Gray, Joe W. Heiser, Laura Madeline Korkola, James Mills, Gordon B. (co-PI) [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Extrinsic Perturbations of Cell Physiology and Associated Regulatory Networks @ Oregon Health & Science University
DESCRIPTION (provided by applicant): The overall goal of the Data Generation Aim is to produce high quality data measuring phenotypes, protein and phosphoproteomics, and RNA expression in 30 cell lines grown on diverse microenvironments (ME). This approach will significantly enhance the LINCS data matrix by providing phenotypic, proteomic, and transcriptomic data for cell lines under unique ME conditions. Furthermore, the data will be utilized for subsequent generation of cellular network signatures in the Data Analysis Aim. Sub aim 1.1 will be generate 10 different phenotypic endpoints for 30 cell lines grown on 3,060 MEs. We will utilize Microenvironment Microarrays (MEMA) to assess the effects of the ME on proliferation, apoptosis, differentiation state, cell binding, and motility in each cell line. Statistical analysis will identify 50 significnt MEs for validation each year in years 2-6 in sub aim 1.2.A (total of 250 conditions). Each of the 50 ME conditions will be re-tested with the same endpoints at a second site using MEMA technology to provide independent validation of the primary results. At the same time, the cells will be tested using the 50 ME conditions on a second set of arrays designed to model the elastic modulus of human tissues to determine the effects on phenotypes of the matrix stiffness. From the 50 conditions tested in the validation aims, 30 of the most concordant between the primary and validation sites will be selected annually for analysis by Reverse Phase Protein Array (RPPA) aim 1.2.B and RNA expression analysis (aim I.2.C.). The RPPA aim will produce data using 500 validated antibodies against proteins and phosphoproteins in key signaling pathways under each of the ME perturbations. The RNA expression analysis will examine 1000 key genes using Luminex bead technology developed by the LINCS group at the Broad Institute, who will perform the same analysis for us using RNA prepared from each of the cell lines grown under the ME conditions. In total, the RPPA and RNA expression analysis will generate data for 150 different ME conditions under 2 different elastic moduli. All data will be carefully curated, with extensive metadata collected, and provided to the LINCS community for populating the data matrix.
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0.912 |
2014 — 2019 |
Gray, Joe W. Heiser, Laura Madeline Korkola, James |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Outreach @ Oregon Health & Science University |
0.912 |
2017 — 2021 |
Heiser, Laura Madeline |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Managing Microenvironment-Mediated Heterogeneity and Resistance @ Oregon Health & Science University
ABSTRACT ? Project 2 Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, characterized by significant intratumor heterogeneity, limited treatment options, and poor patient outcome. The inability to effectively treat TNBC is thought to be in part due to its heterogeneity, as cells are highly plastic and able to respond rapidly to therapeutic insults to steer into drug resistant states. One aspect that is likely to strongly influence TNBC plasticity, heterogeneity, and response to therapy is the microenvironment (ME) in which cells reside. Interactions with extracellular matrix proteins or soluble factors like growth factors and cytokines can profoundly change phenotypic properties of TNBC cells, and mounting evidence suggests that such ME factors also influence response to therapy. We hypothesize that the ME impacts therapeutic response of TNBC, and that consideration of signals from the ME in treatment decisions are likely to lead to improved therapeutic control and patient outcomes. We propose to couple experimental assessment of TNBC response to targeted therapeutics in the presence of defined combinatorial ME perturbations (MEPs) with concomitant expression profiling and computational approaches to define underlying pathway signatures to identify vulnerabilities in residual cancer cells that could be exploited for therapeutic benefit. This will be accomplished in three Aims. In Aim 1, we will utilize a novel technology known as microenvironment microarrays (MEMA), which allow for the rational interrogation of thousands of unique ME for effects on cellular phenotypes in a single assay, to identify MEPs that confer resistance to six targeted therapeutics in TNBC cell lines and primary patient derived xenograft (PDX) samples. In Aim 2, we will perform expression profiling by RNA-Seq at fixed time points on TNBC cells grown in the presence of resistance conferring MEPs plus therapeutic and use computational approaches to identify underlying reduced dimensionality network signatures (PREdic-tors of CEllular Phenotypes to guide Therapeutic Strategies, PRECEPTS) that are altered as a result of interactions of cells with MEP and drug. These altered PRECEPTS signatures represent candidates for therapeutic intervention, and will be tested using drug combinations in an attempt to overcome ME-mediated resistance. In Aim 3, we will perform dynamic imaging and expression profiling of the response of TNBC cells to resistance conferring MEPs plus drug and identify PRECEPTS signatures that are dynamically altered. Such PRECEPTS signatures represent potential transition vulnerabilities that could be targeted for therapeutic intervention, which we will test experimentally using drug combination treatments of TNBC cells. These approaches will be closely coordinated with those of Projects 1 and 3 in the use of common cell lines, drugs, and reagents and to maximize the information that we derive from the experiments. This approach should enable the discovery of new drug combinations that could be deployed clinically to improve outcome in TNBC patients with primary and disseminated disease.
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0.912 |
2021 |
Demir, Emek Gray, Joe W. Heiser, Laura Madeline Sears, Rosalie C Tomlin, Claire J |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Measuring, Modeling and Controlling Heterogeneity @ Oregon Health & Science University
ABSTRACT - Overall The overall goal of the Measuring, Modeling and Controlling Heterogeneity Center in the Cancer Systems Biol- ogy Consortium (M2CH-CSBC Center) is to improve management of triple negative breast cancer (TNBC) by developing systems level strategies to prevent the emergence of cancer subpopulations that are resistant to treatment. We postulate that heterogeneity arising from epigenomic instability intrinsic to cancer cells and di- verse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance. We will learn how intrinsic and extrinsic factors influence differentiation state, proliferation and therapeutic re- sponse in TNBC through experimental manipulation and computational modeling of cancer cell lines, 3D engi- neered multicellular systems, xenografts and clinical specimens. We will deploy single cell `omic and imaging technologies that allow quantitative assessment of molecular, cellular, and structural heterogeneity. We will interpret these data using computational models that define control networks and structures in heterogeneous systems as well as transitions between states of therapeutic resistance and sensitivity. This will be accom- plished in three related Projects and three Cores. Project 1 will focus on measuring and managing resistance- associated heterogeneity intrinsic to cancer cells. Project 2 will focus on identifying resistance-associated sig- nals from the microenvironment and on mitigating effects from these signals on therapeutic response. Project 3 will apply spatial systems biology approaches to TNBC specimens and multicell type models thereof to dis- cover molecular control networks that influence how cell intrinsic plasticity and microenvironment signaling al- ter therapeutic responses in complex tissues. All three Projects will include analysis of 5 core cell lines (HCC1143, HCC1599, MDA-MB-468, SUM149PT, and HCC1806), 5 patient derived cultures, and 6 FDA ap- proved, pathway-targeted drugs (afatinib, ruxolotinib, trametinib, BYL719, cabozantinib, and everolimus). The computational network discovery, data integration, spatial systems analysis and modeling approaches are the same in all Projects and serve to integrate the work of the overall M2CH-CSBC Center. Multiple integrative computational strategies are proposed to identify candidate heterogeneity control networks. These include analysis of existing genomic, epigenomic, pharmacologic response, and metabolomic characteristics of prima- ry tumors and models thereof. An Imaging Management and Analysis Core will provide infrastructure and image analytics that will enable efficient image data management, quantitative analysis of image features, and visualization of images and metadata generated using multiscale light and electron microscopy. An Outreach Core will make educational materials, experimental and computational tools and data available to the CSB Consortium, to the CSBC/PS-ON Coordinating Center and to the broader scientific community. An Administrative Core serves as the organization, integration, and evaluation hub of the M2CH-CSBC Center.
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0.912 |