As determined by the cancer research community and NCI, inefficiencies and inaccuracies of existing methods for drug testing are critical obstacles preventing development and clinical translation of new drugs to dramatically improve cancer therapy (Provocative Question 17). To overcome these obstacles, we will develop a new 3D cell culture model of disseminated breast cancer cells in the bone marrow microenvironment. Our focus on the bone marrow microenvironment is driven by the high frequency of disseminated cancer cells even in patients with seemingly localized primary tumors, limited activity of drugs against metastases relative to primary tumors, and >90% of cancer mortality caused by metastatic disease. Our model will incorporate multiple types of human bone marrow stromal cells, including mesenchymal stem cells, endothelium, and osteoblasts. One or more of these cell types form protective niches that may confer drug resistance to metastatic breast cancer cells through intercellular signaling pathways. We will optimize culture conditions to reproduce hypoxia normally present in human bone marrow, using an innovative imaging technique to quantify oxygenation within 3D spheroids. We will test activity of standard chemotherapeutic drugs in breast cancer and promising molecularly-targeted compounds against human cell lines representative of intrinsic molecular subtypes of breast cancer integrated into 3D bone marrow spheroids. We also will test compounds against primary human breast cancer cells passaged only as mouse xenografts and correlate responses in 3D culture with patient outcomes. For both cell lines and primary tumor specimens, we will use advanced optical imaging methods to measure drug targeting, potential mechanisms of drug resistance, and heterogeneous responses of breast cancer cells to treatment. We will answer Provocative Question 17 by accomplishing the following specific aims: 1) develop an advanced 3D culture system to analyze treatment of disseminated human breast cancer cells in bone marrow;2) quantify effects of compounds on breast cancer cell lines representative of molecular subclasses of human breast cancer and tumor-initiating cells;3) determine activities of compounds against primary patient tumor samples. Collectively, this research will establish a facile, inexpensive, reproducible model to test potential cancer drugs and accurately match compounds with patient subpopulations highly likely to respond to treatment. The strategy will accelerate clinical translation of new, more effective cancer drugs while reducing costs of drug development.

Public Health Relevance

This research will develop an improved approach for testing potential new drugs against breast cancer cells in bone marrow, a common site of metastatic disease. Our approach can be used for many other types of cancer, so this research will lead to better therapies for multiple patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA170198-01
Application #
8374192
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Program Officer
Alley, Michael C
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$378,626
Indirect Cost
$130,693
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Luker, Gary D; Nguyen, Huong Marie; Hoff, Benjamin A et al. (2016) A Pilot Study of Quantitative MRI Parametric Response Mapping of Bone Marrow Fat for Treatment Assessment in Myelofibrosis. Tomography 2:67-78
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Stacer, Amanda C; Wang, Hanxiao; Fenner, Joseph et al. (2015) Imaging Reporters for Proteasome Activity Identify Tumor- and Metastasis-Initiating Cells. Mol Imaging 14:414-28

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