Neural Stem Cell Therapy for Breast Cancer Brain Metastases

Institution: Scripps Research Institute
Investigator(s): Brunhilde Felding, Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0122 Award: $302,085
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2006)
Today, breast tumors can be detected early and removed with advanced surgery and treatment, but current therapies cannot prevent or eradicate breast cancer after metastatic spread to distant organs. The prognosis is very poor if breast cancer spreads to the brain. As a shielded “sanctuary site,” the brain may harbor breast cancer cells which resist current treatments and can develop into satellite tumors, known as metastases, long after chemo-, radiation, or immuno- therapies have been applied. The patient’s situation can be managed in the clinic only for a few weeks or months before becoming fatal. Our project seeks to provide new hope for patients, as we will try to inhibit breast cancer brain metastases through an innovative approach based on stem cells, the body’s own natural mechanism for healing and regeneration.

Our hypothesis is that brain metastases in breast cancer patients can be targeted with neural stem cells, which are known to seek out diseased or cancerous areas in the brain. We will determine where, when, how often, and in what number neural stem cells need to be administered to target breast cancer cells within the brain tissue. We will “arm” neural stem cells with a “pro-drug” strategy so they can locally convert a harmless drug into a highly toxic drug to eradicate breast cancer brain metastases. Finally, we will investigate whether treatment with neural stem cells is safe. We will track the neural stem cells, analyze how they behave in animal subjects, and examine if the administered stem cells affect any normal healthy tissues.

We are collaborating with Dr. Evan Snyder at The Burnham Institute, who brings expertise in neural stem cells biology to this project. In preliminary work at Scripps, we have established human breast cancer cell and mouse models that mimic the development of brain metastases in breast cancer patients. We also have an armed neural stem cell model with documented therapeutic properties and a non-invasive imaging system that allows us to follow the breast cancer cells and stem cells in live mice to analyze their response to treatment. We will use female mice that accept human cells and inject them with our patient-derived breast cancer cells, which have a tendency to spread to the brain. The mice will be imaged repeatedly to find out when brain metastases have developed. Once that is the case, we will inject neural stem cells. These stem cells have been engineered to contain a “reporter gene” that allows us to track them in our mouse “patients” by imaging. The stem cells also contain an introduced protein that can convert a non-toxic pro-drug into its toxic form that kills dividing cells such as the tumor cells. Once the stem cells have migrated to the metastatic lesions, we will treat the mice with the harmless pro-drug. We expect that this will kill the tumor cells in the vicinity of the stem cells without affecting the normal brain cells or the stem cells themselves, as long as they do not divide. Should that be the case, however, the treatment will also kill the stem cells and thereby function as a built-in safety mechanism. The effects of this treatment will be followed through non-invasive imaging of the live mice and, later, at the cellular level under the microscope.

The proposed project, if successful, will demonstrate for the first time that neural stem cells can be used to eliminate metastatic breast cancer cells that have spread to the brain. This would represent a breakthrough for treating advanced breast cancer.

Final Report (2007)
Overview of topic:
Brain metastases are among the most feared complications in breast cancer. Despite today's advances in early detection and treatment, nearly 30% of patients with advanced breast cancer are eventually diagnosed with brain lesions, making breast tumors the main source of metastatic brain disease in women. As a shielded 'sanctuary site', the brain may harbor breast cancer cells that resist current treatments and can develop into metastases, long after chemo-, radiation- or immuno therapy have been applied. This situation can be controlled in the clinic only for a few weeks or months, often with severe side effects, which add to the trauma caused by the disease. Our project seeks to provide new hope as we try to inhibit breast cancer brain metastases through an innovative approach by harnessing neural stem cells, the body's own mechanism for healing and regeneration in the brain.

Questions addressed and barriers that were overcome:
The data from this project support our original hypothesis that breast cancer brain metastases can be targeted with neural stem cells. We documented that such stem cells seek out cancerous areas in the brain and follow spreading breast cancer lesions within the brain tissue. Detailed investigations on where, when, how often and in what number neural stem cells need to be administered to an experimental "patient" to target breast cancer cells the brain and central nervous system will reveal if this experimental therapy has potential for translation into the clinic.

Major accomplishments:
We have developed human and mouse tumor cell systems and detection methods that allowed us to generate experimental models for studying breast cancer brain metastasis. Our models are based on human tumor cells and their brain seeking variants that we isolated in experimental mice. The tumor cells and the neural stem cells were genetically labeled with distinct luciferase genes (i.e., making the location of tumor and stem cells visible using fluorescent light), making it possible to differentiate the two cell types in live animals and follow the progression of metastasis development and the ability of the stem cells to track the tumor cells in real time. Using this novel technology and detailed histology, we were able to document that implanted neural stem cells seek out even widespread metastatic breast cancer lesions within the brain tissue. In summary, we demonstrated that
  1. we can generate experimental patients in a mouse model with disseminated metastatic breast cancer in the brain and central nervous system,
  2. our tumor cell models spread within the brain tissue from intracranial implants and from the blood stream after injecting the cancer cells into the carotid artery, allowing us to mimic situations of breast cancer patients with widespread brain metastasis,
  3. a neural stem cell model expresses cytosine deaminase and can kill breast cancer cells in culture,
  4. these neural stem cells localize precisely to metastatic lesions in the brain of immune deficient mice, and that
  5. the tumor seeking property of the stem cells is even stronger in immune competent mice, which closely reflect the clinical situation of breast cancer patients with brain metastasis.

Plans for continuation:
The overall goal of the continuing work is to fully explore the efficacy, specificity, and safety of a neural stem cell based therapy against breast cancer brain metastases, and to translate this novel therapeutic approach into the clinic.