October 22, 1999

Award boosts patient-oriented breast cancer research

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Dr. Brenda Nicholson recently examined patient Carol Butler at the Vanderbilt-Ingram Cancer Center. (photo by Dana Johnson)

Award boosts patient-oriented breast cancer research

Dr. Brenda P. Nicholson, assistant professor of Medicine, has received a five-year Clinical Associate Physician award from the National Institutes of Health to pursue clinical breast cancer research. The award is part of NIH efforts to promote the career development of young patient-oriented investigators.

"The nation has very few full-time patient-oriented investigators left, and it is estimated that fewer than two dozen are women. That is why we are so pleased when such awards are made to our institution," said Dr. David Robertson, professor of Medicine, Pharmacology, and Neurology and director of the Clinical Research Center.

Nicholson will utilize the CRC facilities for her studies, which include collaborations with several of her colleagues in the Vanderbilt-Ingram Cancer Center. Among these projects:

• With Dr. Carlos L. Arteaga, Ingram Professor of Cancer Research, she will test whether a combination of tamoxifen and Herceptin is more effective than tamoxifen alone for treating patients who have estrogen-responsive tumors and metastatic breast cancer.

The monoclonal antibody Herceptin blocks the growth factor receptor HER-2. Pre-clinical data suggest that the ability of tumors to develop resistance to the anti-estrogen tamoxifen may be via the HER-2 pathway, Nicholson said. Nicholson and Arteaga believe that combining Herceptin and tamoxifen will improve response rate and time to treatment failure.

They will also assess various molecular markers in the cancerous cells from biopsy material obtained before and during treatment. By evaluating markers for cell cycle arrest, apoptosis (cell death), cell proliferation, and HER-2, they hope to understand the mechanism involved in tamoxifen resistance.

• With Dr. Jeffrey T. Holt, professor of Cell Biology and assistant professor of Pathology, Nicholson will test BRCA1 gene therapy in patients with chest wall recurrences of breast cancer. Mutations in the BRCA1 gene are linked to hereditary breast cancer.

"What's interesting is that even in sporadic (non-hereditary) breast cancer, which is about 90 percent of breast cancers, expression of the BRCA1 gene is reduced," Nicholson said. "This suggests that the BRCA1 gene product normally acts as a tumor suppressor, and that inhibition of its activity has an effect on developing breast cancer."

A functioning BRCA1 gene might therefore block cancer. In earlier work, Holt demonstrated that established tumors in mice shrink following injection of the BRCA1 gene.

In earlier clinical trials with BRCA1 in ovarian cancer patients, the vector used to deliver the gene was highly susceptible to destruction by the immune system. Nicholson and Holt's Phase I study will use a newly developed vector-BRCA1 gene combination that they believe will be resistant to the immune system. They will inject the gene directly into the chest wall tumors in patients with this breast cancer recurrence and look for a response. Concurrently, they will evaluate methods to deliver the gene systemically in mice.

"Our goal is to see if gene therapy might work in patients who have breast cancer. If it appears to work in this setting, the idea and the hope is that it can be further developed so that we can give the gene systemically, because breast cancer is a systemic disease," Nicholson said.

• With Dr. Bapsi Chak, assistant professor of Radiation Oncology, Dr. Mark C. Kelley, assistant professor of Surgery, and Jennifer A. Pietenpol, Ph.D., assistant professor of Biochemistry, Nicholson will evaluate the ability of Taxol to sensitize cancer cells to radiation. It is thought that Taxol shifts cells to a cell cycle stage called G2/M arrest that is particularly sensitive to radiation. Nicholson and colleagues will analyze an initial breast cancer biopsy, then treat with Taxol and analyze another biopsy for percent of cells in G2/M arrest.

"Our hypothesis is that those patients whose tumors have a higher percent of cells put into G2/M arrest will be more sensitive to our treatment," Nicholson said. The patients will receive three Taxol treatments followed by combination Taxol/radiation therapy, surgery, and additional chemotherapy. Chemotherapy and/or radiation treatment to shrink tumors prior to surgery is known as neo-adjuvant therapy.

"Neo-adjuvant therapy is not a unique approach. What's unique about our study is the development of molecular markers to predict responsiveness to treatment," Nicholson said. "In the future we hope to use markers to predict tumor cell response, so that we can better individualize patient treatment."

In all of her research projects, Nicholson strives to bridge the laboratory bench and the patient bedside.

"I try to work with the basic scientists to develop techniques that are clinically useful," Nicholson said.

"If I can serve to bring together basic scientists and clinicians, then I think we'll be able to move things forward more rapidly and our patients will ultimately benefit."

Nicholson earned her medical degree from Wright State University in Dayton, Ohio and completed her internship and residency in internal medicine at the Bowman Gray School of Medicine at Wake Forest University. She came to Vanderbilt for a three-year Hematology-Oncology fellowship and joined the faculty in 1998.

Nicholson credits her mentor Dr. David H. Johnson, Cornelius Abernathy Craig Professor of Oncology, deputy director of the Vanderbilt-Ingram Cancer Center, and director of Medical Oncology, with giving her "tremendous opportunities" that launched her into a career of patient-oriented research.

"By doing translational research, I feel like I get the best of both worlds."