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First Test of p53 Gene Therapy in Breast Cancer Opens

First Test of p53 Gene Therapy in Breast Cancer Opens
M. D. Anderson News Release 11/05/02

For the first time, the power of a novel gene therapy drug to treat locally advanced breast cancer is being tested in a clinical trial at The University of Texas M. D. Anderson Cancer Center.

The trial combines the drug, Advexin, with standard chemotherapy treatment"neoadjuvantly"– that is, before either surgery or radiotherapy treatment.Researchers hope such an initial use of the gene therapy/chemotherapy combination will boost cure rates and overall patient survival.

Advexin is a drug that researchers believe may be able to both kill cancercells directly as well as stimulate the immune system to attack additional tumor cells. It is designed to use the p53 gene – a potent natural anti-tumor gene – to kill cancer cells and to stop tumor growth without harming normal cells.

The drug, in clinical trials when administered alone or with chemotherapy or radiotherapy in the treatment of head and neck cancer, has shown encouraging results. In  Phase II trials, when combined with radiation therapy, in patients with non-small cell lung cancer there was suggestive evidence of enhanced anti-tumor activity. It has never before been tested in breast cancer in such a comprehensive manner.

Under M. D. Anderson's Department of Breast Medical Oncology, this Phase II clinical trial is recruiting 60 patients with stage III A-B or localized stage IV breast cancer.  The drug's developer, Introgen Therapeutics, Inc. of Houston, Texas, is sponsoring the trial.

Researchers are conducting the trial to specifically determine if adding the drug to a standard chemotherapy regimen of docetaxel plus doxorubicin increases the ability of the chemotherapy to kill breast cancer cells and eradicate tumors. Another objective of the study is to determine the degree to which this combination treatment contributes to the death of cancer cells (known as therapy-induced apoptosis) in breast cancer patients.

While doxorubicin and docetaxel have been an effective treatment of locally advanced breast cancer, "new approaches are needed to further improve complete remission and patient survival rates," says Massimo Cristofanilli, M.D., assistant professor in M. D. Anderson's Department of Breast Medical Oncology, and principal investigator. "This study will determine if Advexin can enhance the efficacy of combination chemotherapy increasing the chance of complete remission."

The p53 gene interferes with cancer cells because, as a tumor suppressor gene, it carries instructions to make a protein (also called p53) known to be an important part of the body's cellular response to DNA damage caused by tumors. In cells that have undergone DNA damage, the p53 protein acts like a "brake pedal" and halts cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide (apoptosis) to prevent genetically damaged cell from growing out of control.

Research has shown that damaged p53 genes occur with high frequency in locally advanced breast cancer (50 percent to 55 percent) compared with early breast cancer (25 percent to 30 percent), suggesting that it may be a late phenomenon in breast cancer tumor formation.  The presence of damaged p53 genes is associated with more aggressive tumors, early metastasis and decreased survival rates.

Locally advanced breast cancer accounts for 5 percent to 15 percent of newly diagnosed breast cancer cases in the United States, and represents a category of patients who desperately need improved treatment options.

One of the advantages to use of Advexin in combination with chemotherapy is that the drug is minimally toxic, says Gabriel Hortobagyi, M.D., chairman of the Department of Breast Medical Oncology. Extensive experience with Advexin in preclinical and Phase l trials has "demonstrated its safety, and we also know that Advexin  can kill cancer cells and stop tumor growth without harming normal cells in human trials for other cancers," he says.

In the study that began in January, all patients are receiving docetaxel plus doxorubicin together with Advexin every three weeks for four treatment cycles.  On the first day of each treatment cycle, patients will receive doxorubicin 50 mg/m2 IV in 15 minutes immediately followed by docetaxel 75 mg/m2 in one hour. Patients will receive injections of Advexin directly into their tumors on the first two days of each cycle.

Introgen Therapeutics, Inc. controls patents for the use of chemo-gene combination therapy in general and for use of Advexin drug therapy in combination with the taxanes, Taxotere (docetaxel) and Taxol (paclitaxel).

Prospective participants or referring physicians who would like to learn more about the study, as well as additional inclusion requirements, should call the M. D. Anderson Information Line at (800) 392-1611.


© 2015 The University of Texas MD Anderson Cancer Center