Survivin: Target for Breast Cancer Brain Metastases

Institution: University of Southern California
Investigator(s): Florence Hofman, Ph.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11IB-0145 Award: $242,854
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2005)
Metastatic breast cancer to the brain is common in advanced disease and is associated with a poor prognosis. Chemotherapeutic agents, useful in treating systemic breast cancer, have little effect in brain metastases, because the blood-brain-barrier is impenetrable to most drugs. The tumor vasculature also provides necessary nutrients for tumor growth. Preliminary data show that survivin, an inhibitor of apoptosis protein, is over expressed in tumor-associated brain endothelial cells (TuBEC), making these cells resistant to cell death. Blocking survivin production induces apoptosis in other systems. The goal of this project is to induce TuBEC cytotoxicity by targeting survivin. This would destroy the BBB and tumor vasculature thereby eliminating breast cancers in the brain.

Our objectives are to determine whether: 1. reducing expression levels of survivin in tumor-associated TuBEC will induce these cells to undergo spontaneous apoptosis. 2. the results of reducing expression levels of survivin protein in TuBEC will alter their angiogenic properties. 3. reduced expression of survivin in TuBEC will disrupt the blood-brain-barrier and reduce tumor growth in an animal tumor model.

The cell culture model will use purified, characterized, primary cultures of human endothelial cells derived from metastatic breast cancer to the brain. The animal model will utilize a novel system of breast tumor cells co-cultured with tumor-associated brain endothelial cells. Survivin production in endothelial cells will be permanently blocked using small interfering RNA (siRNA). Survivin content of cells will be determined by antibody staining and Western blot analysis. Cell apoptosis will be determined using standard assays. Tumors will be evaluated by size, vascular structures, and extent of blood-brain-barrier permeability.

At this time there are limited effective therapies for patients with metastatic breast cancer to the brain. These studies will provide a new approach to treating metastases in the brain, because it focuses on the tumor-associated brain endothelial cells, the blood-brain-barrier (BBB) itself. The goal is to disrupt the BBB, and destroy the tumor vasculature. This will open the possibility for using a wide range of presently available chemotherapeutic agents for brain metastases. Since anti-survivin therapy may well be an effective anti-angiogenic therapy as well, this agent in conjunction with other drugs at lower doses may be useful in blocking tumor growth.

Final Report (2007)
Metastatic breast cancer to the brain is a serious problem, with poor prognosis. To stop breast tumors from growing, tumor cells must be killed and the blood supply which nourishes the tumors must be halted. Existing therapies are reasonably effective in stopping primary breast cancer growth. However, these drugs cannot enter the brain because of brain's impermeable blood vessels. Therefore, an effective strategy for treating metastatic brain cancer is to destroy blood vessels within the tumor. Survivin, protein found in tumor blood vessels, causes these cells to be resistant to drugs. Thus reducing survivin production will make the tumor-associated blood vessel cells susceptible to the currently used chemotherapy. Destruction of these blood vessels will impede tumor growth and, by making the vessels porous will also allow a direct access of chemotherapeutic drugs to the tumor cells thereby eliminating the tumor.

We have used two systems to determine whether reducing survivin in tumor-associated blood vessels cells will alter their functions.

(1) We have reduced survivin in purified blood vessel cells from human metastatic breast cancer to the brain, and tested for cell death and ability to make functional vessels. We have checked if cells with reduced surviving are more vulnerable to chemotherapeutic drugs. Our results showed that reducing surviving levels in tumor brain endothelial cells (TuBEC) using a siRNA approach would increase their sensitivity to temozolomide (an alkylating agent) treatment.

(2) We have determined how human tumor-associated vessels cells with reduced survivin function in supporting human breast cancer growth in an intracranial mouse model of human breast tumor developed in this laboratory. This model focuses on the effects of vascular cells on tumor growth. These studies are still in progress, and will show whether survivin can be reduced in the vascular cells, and implanted into the rodent brain. Thus, if successful, this novel drug combination will be immediately clinically relevant.

In discussions with patient advocacy representatives, it was clear that this proposed research addresses the needs of the patient community. While there is intense research into different treatments for breast cancer, there is a lack of research focusing on metastatic breast cancer to the brain, which involves 10-15% of breast cancer patients. This is a problem because commonly used radiation therapy may cause significant mental impairment; while conventional therapies are less effective. The advocate especially noted the reservation often expressed by patients to intensive radiation therapy, which may leave persons intellectually and psychologically altered. Thus therapies that focus on efficient, effective and noninvasive treatment of metastatic breast cancer to the brain are welcomed.

Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme.
Periodical:Neurosurgery Focus
Index Medicus: Neurosurg Focus
Authors: Charalambous C, Chen TC, Hofman FM
Yr: 2006 Vol: 20 Nbr: 4 Abs: Pg:E22