- Overall We propose to create an Omic and Multidimensional Spatial (OMS) Atlas that will enable discovery of mechanisms of resistance that arise in individual patients with metastatic breast and prostate cancer during treatment with current generation targeted therapeutic combinations and immune checkpoint inhibitors. The OMS Atlas is motivated by the fact that these treatments typically are only transiently effective in the metastatic setting. Possible resistance mechanisms may be intrinsic to the tumor cells or derive from the diverse microenvironments in which the tumor cells live. The OMS Atlas will focus on elucidating these resistance mechanisms in three specific current generation clinical scenarios: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with a CDK4/6 inhibitor in combination with endocrine therapy, (b) triple negative breast cancer (TNBC) undergoing treatment with a PARP inhibitor and an immunomodulatory agent, and (c) castration resistance prostate cancer (CRPC) undergoing treatment with enzalutamide. We will accomplish this through work in four areas. A Biospecimen Unit will prospectively collect, manage, and distribute longitudinal clinical information, blood, and biopsies from 20 patients from each of two metastatic breast cancer cohorts and one prostate cancer cohort that will be analyzed to create three OMS Atlases. The biopsies will be preserved to enable analyses using multiple characterization modalities. A Characterization Unit will analyze (a) OCT frozen specimens using Topographic Single Cell Sequencing (TSCS) and Single-cell Combinatorial Indexing ATAC- seq (sci-ATAC-seq) to elucidate spatially defined genomic changes and chromatin accessibility in single cells, (b) formalin fixed, paraffin embedded (FFPE) specimens using multiplex immunohistochemistry (mIHC) to assess the immune microenvironment and cyclic Immunofluorescence (cycIF) to assess the composition and molecular states of tumor cells and their microenvironments, and (c) paraformaldehyde fixed, resin embedded (PFRE) specimens using a Focused Ion Beam Scanning Electron Microscope (FIB-SEM) to identify ultrastructural changes in 2D images and targeted 3D images with 4-nm resolution. Omic characterization of the same tumor samples will be provided by the SMMART Program. A Data Analysis Unit will develop and deploy tools to (a) manage, analyze, and visualize Tier 1 data comprised of raw sequence data and images to generate unimodal Tier 2 results, (b) integrate omics and imaging data through crosswise mapping to create single timepoint tumor maps and quantify systems biological functions of tumor cellular subpopulations to generate Tier 3 results, and (c) explore differences between pre- and on/post-treatment tumor maps to reveal mechanisms of resistance that comprise Tier 4 results. We will collaborate with private sector partners to evaluate and adopt next generation technologies that increase analytical power and speed and reduce costs. The Administrative Unit will facilitate the coordination, operation, interaction, and evaluation of activities within the OMS Atlas and between OMS Atlas scientists and the HTAN.

Public Health Relevance

Treatments of metastatic breast and prostate cancers typically are not durable. The OMS Atlas project will apply state of the art analysis tools to tumor samples taken at multiple times during treatment in order to identify changes in the components and structures of these cancers that enable them to escape therapeutic control. This information will guide the development of new therapeutic approaches that can be used to reestablish control and develop new diagnostic procedures that will guide the use of these treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Resource-Related Research Multi-Component Projects and Centers Cooperative Agreements (U2C)
Project #
5U2CCA233280-02
Application #
9788351
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hughes, Shannon K
Project Start
2018-09-19
Project End
2023-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Overall Medical
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239