DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

New Diagnostic and Therapeutic Approaches to Eradicating Recurrent Breast Cancer

Principal Investigator: MCALLISTER, SANDRA S
Institution Receiving Award: BRIGHAM AND WOMEN'S HOSPITAL, INC.
Program: BCRP
Proposal Number: BC130835
Award Number: W81XWH-14-1-0191
Funding Mechanism: Era of Hope Scholar Award
Partnering Awards:
Award Amount: $4,199,040.00


TECHNICAL ABSTRACT

Current primary breast cancer staging algorithms do not adequately predict the risk of breast cancer recurrence and there are no curative treatment options for patients once they do relapse with metastatic disease. This project is designed to provide a basis for developing new non-invasive tests that will allow oncologists to more accurately identify breast cancer patients who at risk of relapse and to develop new treatment therapies that can be given to those patients before disease recurs.

Some breast cancer patients have no evidence of metastatic disease at the time of their original diagnosis and treatment, yet some of these patients will experience metastatic disease months, years, or even decades later. At this point, harsh chemotherapy is the only treatment approach currently available to these women. Studies have shown that less than 1% of disseminated tumor cells (DTCs) that spread throughout the body are eventually able to form an overt tumor while the vast majority of DTCs remain inconsequential. While various technologies have been developed to isolate DTCs from the blood or bone marrow of cancer patients, we currently have no idea which, if any, of these DTCs is responsible for relapse. Previous work in our lab, using breast cancer cells, patient tumor samples, and mouse models, revealed that indolent DTCs respond to the body's systemic cues to convert to a malignant state. Circulating cytokines and bone marrow-derived cells (BMDCs) are responsible for imparting these systemic cues to the DTCs. Importantly, we found that these tumor-supportive BMDCs are not present in the blood of mice without breast cancer.

We hypothesize that certain disseminated tumors are able to respond to specific systemic and microenvironmental cues to become malignant metastases and that neutralizing these tumor-promoting processes will provide a therapeutic strategy to save lives. Our studies are designed to: (1) Establish ways to distinguish DTCs with malignant potential from those that will remain indolent using models that closely resemble the natural progression of breast cancer recurrence. To do so, we will utilize novel molecular barcoding approaches to extensively profile breast cancer DTCs at critical stages during metastatic progression in our mouse models. (2) Define mechanisms of breast cancer relapse by which BMDCs promote outgrowth of otherwise indolent tumors by using our unique cell culture system that enables us to determine the effects of BMDCs (from bone marrow aspirates and peripheral circulation) on DTC malignancy in a high-throughput manner. (3) Identify drugs that prevent indolent DTCs from responding to tumor-promoting bone marrow derived cells to become malignant. We will use breast cancer cells, mouse models of breast cancer, patient blood samples, and patient breast cancer tumor tissues in order to test these new strategies in the preclinical setting.

The ability to identify life-threatening DTCs and to distinguish them from those that are inconsequential would significantly improve our ability to identify breast cancer patients who are at risk of relapse. Patients harboring the life-threatening DTCs would thus be treated in the adjuvant setting to target deadly DTCs before they develop incurable metastatic disease. Equally importantly, our data should help us to identify patients who harbor inconsequential DTCs and can be spared the toxic side effects of chemotherapy. Likewise, defining the mechanisms by which life-threatening DTCs convert to a malignant state will provide novel opportunities for therapeutic intervention. Discovering drugs that target the harmful DTCs and interrupt the support they receive from circulating bone marrow derived cells will provide new treatment options that would revolutionize the way that breast cancer patients are treated and managed.