For the last 20 years, in her laboratory at the National Cancer Institute, in Bethesda, Maryland, Dr. PATRICIA STEEG has been researching how cancer spreads from the original tumor to other organs. She discovered the first gene that suppresses cancer metastases. Wanting to see the work in her lab make a difference for women with breast cancer, and inspired by her discussions with breast cancer advocates, Dr. Steeg has put together a team of researchers, a Center of Excellence, to speed new treatments from the research lab to women with brain metastases.
Dr. Steeg and Dr. DIANE PALMIERI, a scientist in the Steeg lab, have developed a mouse model with brain metastases in order to test new treatments in mice before they are tried in humans. Dr. Palmieriâ€™s most recent published work, in conjunction with other members of the Center of Excellence, has focused on the role of the Her2 gene in the development of brain metastases. Drs. Steeg and Palmieri are both teachers in Project LEAD, a science course for breast cancer advocates sponsored by the National Breast Cancer Coalition that prepares women to participate in the research process from a patientâ€™s point of view.
Complementing the work of the Steeg lab is the research of Drs. SUYUN HUANG, MIEN-CHIE HUNG, JANET PRICE and DIHUA YU from the M.D. Anderson Cancer Center in Houston, Texas. These four researchers have detected important characteristics that appear in aggressive breast cancers, including brain metastases. If these leads are proven to be what drives the development of breast cancer brain metastases, they could provide important new targets for effective drug development. Drs. Price and Huang have developed animal models and cell lines of brain metastasis which will also be used to screen new compounds. Drs. Huang and Yu are internationally recognized experts in Her-2 positive breast cancer.
Drs. QUENTIN SMITH and PAUL LOCKMAN, from Texas Tech University, and Dr. EDWARD NEUWELT, from Oregon Health Science, are world-renowned experts on the blood-brain barrier. While this barrier is natureâ€™s way of protecting the brain from infections, viruses, and toxic substances, the blood-brain barrier also keeps many cancer drugs from getting into the brain. This means that brain metastases, unlike metastases to the liver or lungs, are difficult to treat via drugs that circulate in the bloodstream. Both the general permeability of the blood-brain barrier as well as the action of specific â€śpumpsâ€ť that force chemicals out of the brain once they penetrate into the brain and into the metastases are under study. Dr. Lockman has particular expertise in the use of nanoparticles (tiny molecules to which drugs can be attached) that may be able to penetrate both the blood-brain barrier and the blood-tumor barrier. Dr. Smith has measured the penetrability of different chemotherapeutic agents across the blood-brain barrier and the blood-tumor barrier in rats. He will now extend his findings to mice with brain metastases as well as to women with brain metastases as part of the Center of Excellenceâ€™s first clinical trial. Dr. Neuwelt is developing a strategy of disrupting the blood brain barrier with sugar molecules, thus allowing for drug delivery into the brain. Dr. Neuwelt currently treats people with brain metastases and brain tumors on an experimental basis using this strategy.
It is known that many women with breast cancer have tiny cancerous tumors in their brains, known as dormant micrometastases, that never grow large enough to become symptomatic or to do any damage to the brain. Dr. ANN CHAMBERS, from the London Regional Cancer Centre in Ontario, Canada, is the worldâ€™s leading authority on this enigmatic process known as tumor dormancy. In a series of MRIs, Chambers has shown, in real time, what tumor dormancy looks like in the mouse brain. Only a few of the many micrometastases in the brain develop into tumors that are lethal. Understanding what keeps so many of these tiny tumors in a dormant state holds out great potential for controlling metastatic disease.
Tumor tissues from brain metastases form a crucial research tool for making progress in the prevention, treatment, and eradication of brain metastases of breast cancer. A prerequisite for the successful work of the Center of Excellence has been the location of this scarce tissue. Surgically removed brain metastases, primary tumors from patients who did and did not develop brain metastases, and matched primary tumor tissue and brain metastases (fixed in formalin and embedded in paraffin) are provided by members of the Center of Excellence from Indiana University Cancer Center, Memorial Sloan Kettering Cancer Center and M.D. Anderson Cancer Center under the direction of pathologists Drs. DENNIS SGROI, KENNETH ALDAPE, EDI BROGI, and EYAS HATTAB. Dr. Sgroi will conduct studies of the genes in these tissues using a technique called microarray which measures how much protein is produced by each gene. Two goals are envisioned: first, to identify targets in the tumor tissues that contribute to the development of brain metastases for which drugs can be developed, and second, to find specific gene profiles in primary tumors that metastasize to the brain to identify women at high risk. If researchers can discover which primary tumors will cause brain metastases, it may be possible to develop an effective preventive strategy. Dr. Sgroi will be using laser capture microdissected tumor tissue, a process that allows for the examination of a metastasis on a cell by cell basis.
Key members of this Center of Excellence are the clinical scientists who take findings from the lab and translate them into treatments for patients. One of the main purposes of the Center of Excellence is to link these two components together, thereby speeding the process from animal models to women with breast cancer. The members of our translational scientist team are Drs. ROBERT WEIL, DAVID PEEREBOOM, GEORGE SLEDGE, ANDREW SEIDMAN, DENNIS SLAMON, and KEVIN CAMPHAUSEN. Dr. Weil, a neurosurgeon at the Cleveland Clinic, recently discovered that breast cancer tumors that have an excess number of epidermal growth factor receptors are more likely to metastasize to the brain. He will be collaborating with neuro-oncologist David Peereboom, who is heading up the Center of Excellenceâ€™s initial clinical trial. The goal of this pre-surgical clinical trial is to determine, for the first time, how much of certain drugs used in the treatment of breast cancer actually gets into a human brain metastasis. Dr. MICHAEL KATTAN, our biostatistician, also from the Cleveland Clinic, will help us design clinical trials and biomarker research (studying characteristics of a tumor or metastases) that will come up with meaningful findings.
Dr. George Sledge, from the Indiana University Cancer Center, and Dr. Andrew Seidman, from Memorial Sloan Kettering Cancer Center in New York City, are pre-eminent medical oncologists and translational researchers. They will both be collaborating on tissue studies from their institutions. Dr. Sledge has done pioneering work in the use of important new agents such as Herceptin and Avastin for women with metastatic breast cancer. He is the Breast Cancer Chair of The Eastern Cooperative Group, one of the main clinical trials groups affiliated with the National Cancer Institute. He is known for his excellent presentations to advocates that are given with great wit, thoughtfulness, and integrity, as well as for his dedication to his patients. Dr. Seidman pioneered the use of weekly Taxol for women with metastatic breast cancer, a regime that is both more effective and less toxic than the same treatment given every three weeks. He brings to the Center of Excellence an understanding of the importance of maintaining a good quality of life for women with metastatic breast cancer, and a deep compassion and caring for women with metastatic breast cancer. Dr. Dennis Slamon is world renowned for his role in the development of Herceptin, the first targeted treatment for women who have HER2 positive breast cancer. Herceptinâ€™s success has opened up a whole new way of treating breast cancer.
Radiation has been the mainstay of treatment for women with brain metastases. In hopes of improving the effects of radiation therapy, radiation oncologist Dr. Kevin Camphausen, from the National Cancer Institute, will examine the use of radiation sensitizers, new compounds used in combination with radiation, to see if they can potentiate the effects of radiation.
Both MUSA MAYER and HELEN SCHIFF have been activists in the breast cancer advocacy movement in many different capacities since they were diagnosed with breast cancer almost 20 years ago. Mayerâ€™s advocacy work has focused on women with metastatic breast cancer. She wrote the first book for women living with metastatic disease and their families, and is a daily contributor to the online mailing list BCMets.org where she helps women locate and understand the information they need to make informed treatment decisions. Schiff, a member of SHARE, Self Help for Women with Breast or Ovarian Cancer, has devoted much of her time to organizing and educating breast cancer advocates in the New York City area. She was one of the first advocates to attend medical conferences on breast cancer and report back the proceedings from an advocateâ€™s perspective. Both Mayer and Schiff have served as patient representatives to the Oncologic Drugs Advisory Committee at FDA.
The work of our Center of Excellence, Studies Directed Toward the Eradication of Brain Metastases of Breast Cancer, is funded with a five-year grant of over $17,000,000 from the Department of Defense Breast Cancer Research Program. It is the largest award ever granted by the Breast Cancer Research Program of the Department of Defense