Brain metastases occur in 10%-16% of metastatic breast cancer patients. The incidence is rising, particularly in patients with Her-2 positive tumors. Once diagnosed, patients only have a 20% probability of surviving more than 1 year. Studies estimate that 50% of patients with brain metastases die from their brain lesions, while the other half die of cancer in other parts of their bodies. The treatments for brain metastases--radiation, steroids, some chemotherapy and/or surgery--have limited efficacy and most have significant quality of life complications.

Brain metastases are an "orphan" in breast cancer research: few people study them, few trials are performed, and most brain metastatic patients are ineligible to participate in clinical trials. Why hasn't research addressed this issue? We lack critical tissues to study, we lack model systems, and we lack organization. This Center of Excellence (COE) will form the first community of consumers and investigators centered on brain metastases of breast cancer. The COE has five specific aims.

Aim 1 will build two critical pieces of the infrastructure. First, tissues will be collected from human brain metastases. We need these tissues to find out if molecular alterations identified in a human cell model system are relevant to the heterogeneity of human disease. The second piece of infrastructure will provide models of brain metastasis using a brain seeking derivative of the human MDA-MB-231 cell line, coordinately in the mouse (for quantitation of metastases) and the rat (for brain dissections). This sharing of tissues and expertise is a form of synergy between investigators.

Aim 2 brings brain researchers into breast cancer. Cerebral blood vessels are known to create a formidable barrier to brain delivery of most chemotherapeutic drugs, but are partially compromised in some brain tumors. The importance of this to metastatic tumor drug delivery has never been systematically studied. Some research suggests that this barrier phenomenon creates a drug-free sanctuary that allows tumor growth. Our brain researchers will determine, using our metastasis model and state-of-the-art analytical methods, the extent to which standard breast cancer chemotherapeutic drugs are taken up into brain and brain metastatic tumor, as well as brain on the edge of the tumor. They will investigate to what extent protective systems at the brain blood vessels controlling drug and nutrient delivery are compromised. This information will be invaluable to the design of novel chemotherapeutic agents for brain metastases and is the first step in the rational drug treatment of this disease.

Aim 3 will attempt to identify those molecular events in tumor cells that lead to brain metastasis. We have a list of these potential molecular events and will expand the list using additional analyses. Then we will express the genes in a breast cancer cell line that metastasizes to brain, inject it into the model system from Aim 1, and see if it metastasizes more or less than controls. This will give us a list of functional events to develop preclinically.

Aim 4 brings the findings from Aims 1-3 together. Based on the results of Aim 3, we intend to find compounds to target 10 functional molecular events. We have three compounds already. The brain researchers will work with the breast cancer researchers to find a dosing scheme that will optimize the delivery of these compounds in brain metastases and brain adjacent to metastases. With that scheme, we will determine whether the compound can prevent or treat brain metastases. If, as expected, there is only partial activity, the brain researchers will gear up to identify novel ways to deliver these compounds to the brain metastases. Examples include nanoparticles and temporary disruption of the brain blood vessel barrier.

Aim 5 will evaluate the extent to which selected chemotherapeutic drugs are taken up into human brain metastases in patients undergoing surgical treatment. The drugs and the experiment will be designed to match rodent studies in Aim 2, and will tell us if our rodent models are relevant to human brain metastatic disease and valuable for drug development.

Our experiments are multidisciplinary, synergistic, and innovative. They center on an important problem with no current effective therapy. The consumer advocates have helped design this proposal, and will analyze data, serve on our COE executive committee with equal voting membership, bringing information back and forth from the public to the COE. We will communicate via a password protected website, hold monthly teleconferences and annual meetings. We hope to eradicate this disease.