The Phase II study of 12 women diagnosed with locally advanced breast cancer demonstrated that administering the p53 drug, ADVEXIN, directly to tumors can improve the results of neoadjuvant chemotherapy – a method commonly used to shrink large tumors before surgery or radiation therapy.
"These patients' tumors are typically difficult to treat because of their advanced nature," says Massimo Cristofanilli, M.D., assistant professor of breast medical oncology at M. D. Anderson. "The response to chemotherapy is a mixed bag. After neoadjuvant chemotherapy, some patients have only a few cancer cells left whereas some have a lot of disease, and only 10 percent to 15 percent of patients achieve total remission. Our goal with this study is to increase the pathological remission rate and overall patient survival."
When ADVEXIN was administered by injection, in addition to a standard chemotherapy regimen of docetaxel plus doxorubicin, all 12 patients had dramatic reduction in tumor size with minimal residual tumor cells remaining and no organized nodule. These remaining cells were removed surgically. Of the women studied, none has had a recurrence of cancer since the trial started one year ago, says Cristofanilli.
"The fact that we haven't seen any progression is important for patients with breast cancer," he adds. "This treatment could eventually be applied to breast cancer patients with every stage of disease."
The p53 gene is known as a tumor suppressor gene because it provides a powerful halt signal on cell growth by supplying cells with p53 protein. One of the major roles of this protein is to recognize when the cell has been damaged by mutation and stop cell growth to initiate repair. If the cell is heavily damaged and beyond repair, p53 initiates the cell death pathway to prevent the cell from growing out of control. Scientists refer to this as apoptosis – a normal process that the body uses to eliminate damaged cells, precancerous cells and cells that are no longer necessary.
In about half the cases of aggressive breast cancer, the p53 gene is mutated so that the protein is no longer available in proper amounts to control cell growth, says Cristofanilli. In the cancers where the p53 gene is still normal, the function of the p53 protein can be disrupted in other ways such as sequestration and rapid decay.
Loss of p53 is associated with more aggressive tumors that are resistant to chemotherapy and radiation therapy. Loss of p53 also is associated with early metastasis and decreased survival rates.
ADVEXIN supplies p53 protein in very high concentrations in cancer tissue that selectively kills cancer cells while not harming the surrounding normal cells.
An adenovirus, a common cold virus, is used to carry the p53 gene into cancer cells. The adenovirus has been used extensively as a gene delivery device, or vector, to supply therapeutic genes to cells. The adenovirus survives only long enough to deliver the p53 gene, perhaps only a matter of hours, says Cristofanilli, and can neither replicate, nor insert its genetic material into the cell's DNA. Inside the cancer cell, the p53 gene is translated into the active p53 protein, and cell death is initiated, making this a short-lived and targeted therapy that does not affect normal cells outside the tumor area.
"We have seen very few side effects," says Cristofanilli. "A few patients experienced irritation at the site of injection, but that lasted for only a couple of days."
Introgen Therapeutics, Inc., of Houston, Texas, which is sponsoring the clinical trial, controls patents for the use of chemo-gene combination therapy in general and for the therapeutic use of the p53 gene used alone or in combination with radiation therapy and with chemotherapies including the taxanes, such as Taxotere (docetaxel) and Taxol (paclitaxel), and/or anthracyclines such as doxorubicin and epirubicin.
In the current study at M. D. Anderson Cancer Center, patients receive docetaxel plus doxorubicin together with two injections of ADVEXIN every three weeks for four treatment cycles. Patients diagnosed with stage III A-B or localized stage IV breast cancer are still being recruited for the trial, which is scheduled to include 60 patients.
Initial findings indicate that in addition to direct killing by the p53 genes and proteins, the injections seem to stimulate the immune system to attack the cancer cells.
"Something is happening in the breast with these p53 drug injections that has not been seen before," says Cristofanilli. "In the area of the primary tumor we see immune system cells surrounding the few remaining cancer cells."
However, the role of the immune system needs to be clarified. More patients need to be enrolled and further study of the number of injections required for optimal response will be necessary, he added.
Prospective participants and/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.
Introgen Inc. holds a licensing agreement with M. D. Anderson Cancer Center to commercialize products based on licensed technologies, and has the option to license future technologies under sponsored research agreements. The University of Texas System owns stock in Introgen. These arrangements are managed by M. D. Anderson in accordance with its conflict of interest policies.
Contact: Stephanie Dedeaux or Laura Sussman, (713) 792-0655