Balancing Protumor and Antitumor Immunity To Control Breast Cancer Metastasis

PUBLIC ABSTRACT

The Rationale and Objective for the Proposal:

While current standards of treatment for breast cancer have greatly improved patient morbidity and mortality, the fact that 40% of patients still succumb to the disease underscores the need for improved treatment strategies. There is compelling evidence to suggest that breast cancer dissemination is an early event, and metastases emerge from small numbers of tumor cells that remain in the body but do not grow for many years. Identifying mechanisms regulating the switch from this so-called dormancy stage to metastatic growth has been elusive due to the lack of testable concepts and suitable experimental models. One preferred niche for breast cancer cells is the bone marrow, where the tumor cells survive but are prevented from growing into a mass by the action of the host natural defense, the so-called immune response. Paradoxically, tumor growth and spread is dependent on certain other types of immune responses, namely those that are triggered in the process of wound healing. The emerging picture is that the balance between anti-tumor and pro-tumor immunity determines outcome of cancer. Here, we propose to study in depth the conflict between pro- and antitumor immune responses in the bone of mice with breast cancer. The bone is the first site of breast cancer metastasis, and if we can stop the cancer here then we predict that it will not spread further, and the disease will be controlled. We predict that by tipping the balance in favor of the anti-tumor immune responses, we can protect the patient.

The Ultimate Applicability of the Research:

With the information obtained, we should be in a better position to control the spread of breast cancer by harnessing the natural defenses of the body.

What Types of Patients Will It Help and How Will It Help Them?

Approximately 40% of breast cancer patients will be at risk of disease recurrence in the form of metastases. Controlling disseminated tumor cells is likely to benefit these patients by reducing or eliminating the return of disease.

What are the Potential Clinical Applications, Benefits, and Risks?

The potential clinical application is two-fold. First, using the reaction of the body to cancer, we should be able to get diagnostic and prognostic information, essentially predicting outcome of disease if there were not going to be any intervention. Second, by manipulating the response to cancer, we may be able to control or eradicate the disease.

What is the Projected Time It May Take to Achieve a Patient-Related Outcome?

Essentially, this work could be done in parallel with specimens from patients. However, it is more prudent to get preliminary data in mice and then move to clinical studies. We propose that clinical studies could start upon completion of this work. This may include an interventional goal to test the therapeutic potentials.

If the Research Is Too Basic for Clinical Applicability, Describe the Interim Outcomes.

The research is basic but with direct clinical relevance, as described above.

What are the Likely Contributions of This Study to Advancing the Field of Research?

Identifying mechanisms regulating the switch from few disseminated tumor cells to metastatic disease has been elusive due to the lack of testable concepts and suitable experimental models. We expect the proposed project to advance the field by providing both a testable concept and a relevant animal model for putting the concept to test.