Major Funded Research Projects
OCSSB is the home or a partner to many innovative research projects which have been awarded funding from both federal agencies and private foundations. The current major funded projects at OCSSB are described below.
Characterization of cellular responses to chemical signals in the microenvironment
NIH Microenvironment Perturbagen LINCS Center
Lead Investigators: Joe Gray, Gordon Mills, Laura Heiser, James Korkola
The overall goal of the NIH Common Fund’s Library of Integrated Network-based Cellular Signatures (LINCS) program is to develop a “library” of molecular signatures that describes how different types of cells respond to a variety of perturbing agents. The OHSU LINCS Center was funded for six years in September 2014. It is one of 5 NIH LINCS Centers and involves investigators at OHSU, the MD Anderson Cancer Center and City of Hope. Our Center contributes to the overall LINCS effort by exploring how the biological behaviors of cells are influenced by the regulatory signals they receive from the microenvironments in which they reside.
Understanding Treatment-Resistant Breast Cancers
NCI Cancer Systems Biology Center (CSBC) for Measuring, Modeling and Controlling Heterogeneity (M2CH)
Lead Investigators: Joe Gray, Rosalie Sears, Emek Demir and Claire Tomlin
The overall goal of the NCI Cancer Systems Biology Consortium (CSBC) is to increase our understanding of tumor biology, treatment options, and patient outcome by addressing the complexity associated with cancer through integration of experimental biology and computational and mathematical analysis. The OHSU Center for Cancer Systems Biology involves investigators at OHSU, UC Berkeley, and the MD Anderson Cancer Center. It is one of several NCI CSBC Centers. The goal of the OHSU Center is to improve management of triple negative breast cancer 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 diverse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance.
Clinical Research Trials for Treatment-Resistant Breast Cancers
Prospect Creek Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) Program
Lead Investigators: Gordon Mills, Joe Gray, Raymond Bergan
The goal of this project is to make treatments of cancers of the breast, prostate, pancreas and AML more durable and more tolerable by elucidating and countering mechanisms of resistance as they arise during treatment. This project is funded by a major philanthropic contribution from the Prospect Creek Foundation. In SMMART, patients are followed longitudinally and prescribed combination therapy of 33 FDA-approved drugs by a tumor board considering comprehensive molecular profiling of their tumors and functional assays indicating responsiveness of the patient’s tumor to SMMART drugs. The patient’s serial biopsies are also deeply characterized using a spectrum of omic and imaging analytics, with the purpose of discovering cancer mechanisms of resistance to treatment. All operational aspects of SMMART have been developed and optimized under the ongoing SMMART tissue acquisition protocol. The SMMART 1.0 interventional protocol passed CRRC review and will receive full IRB review once requested revisions are made to the patient consent forms, expected in June 2018. SMMART also includes rules-based precision medicine trials (referred to as SMMART 2.0). Patients have been entered and are receiving treatment (PARP inhibitor + immune modulator) in a SMMART TNBC study. Also, additional arms are being designed and planned (e.g., TNBC patients PARP + MEK inhibitor, PARP + PI3K inhibitor, etc.). Negotiations with pharma for drugs and funding have been successful to date and are continuing.
Mapping Human Cancers
NCI Human Cancer Atlas
Lead Investigators: Joe Gray, Gordon Mills, Jeremy Goecks and Christopher Corless
The NCI, under the auspices of the Beau Biden Cancer Moonshot Initiative is promoting development of multidimensional molecular, cellular, and morphological mapping of human cancers. The OCSSB has submitted a proposal to become a center in the of the NCI Cancer Atlas Project Network. Our project includes collaborators from Harvard Medical School and the MD Anderson Cancer Center and proposes to develop omic and multidimensional spatial atlases of metastatic breast and prostate cancers. It has been reviewed and is under consideration for funding. It takes advantage of the tissues and research and clinical infrastructure in the SMMART program. We are cautiously optimistic about our funding prospects and will know in late 2018.
State-of-the-Art Cryogenic Electron Microscopy
NIH National Cryo-EM Service Center - Pacific Northwest Center for Cryo-EM (PNCC)
Lead Investigator: Eric Gouaux
The NIH has established the Pacific Northwest Center for Cryo-EM (PNCC), a collaboration between OHSU and PNNL, as one of three national cryo-EM service centers to provide access to the technology and support the development of cryo-EM training curricula to build a skilled work-force. The NIH notes that cryo-EM is a method used to image frozen biological molecules without the use of structure-altering dyes or fixatives or the need for crystallization to provide a more accurate model of the molecules and a greater understanding of biological function. Recent advances in cryo-EM technology have made it possible for scientists to obtain detailed images and structures of many biological molecules that cannot be obtained using other methods, like x-ray crystallography. The PNCC builds on the core cryo-EM capability established in the OCSSB and will provide scientists with access to state-of-the-art cryo-EM technology and training, from sample preparation to collection of high-resolution data and computational analysis.
Researching Lethal, Hard-to-Treat Pancreatic Cancer
Brenden-Colson/SU2C Pancreatic Ductal Adenocarcinoma (PDA) Atlas
Lead Investigators: Rosalie Sears and Brett Sheppard
The goal of this project is to enable earlier detection and more durable treatment of pancreatic ductal adenocarcinoma (PDA). The project is supported by a major philanthropic contribution from the Brenden-Colson Foundation and a Stand Up to Cancer (SU2C) grant. We are accomplishing this by elucidating the biological functions of regulatory protein networks in PDA, identifying omic and multiscale molecular assembly changes associated with PDA genesis and progression and identifying omic and multiscale molecular assembly features of PDA cells and associated microenvironments that influence therapeutic resistance in PDA.
Cancer Early Detection Advanced Research Center (CEDAR)
Lead Investigators: Sadik Esener and Paul Spellman
OCSSB faculty and staff provide foundational support for the growing Knight Cancer Institute CEDAR program. This includes analysis technologies and workflow development expertise and participation in developing CEDAR research projects.