Oncology Times:
doi: 10.1097/01.COT.0000291819.90955.9c
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CLINICAL NOTES

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▪ Protein Predictor of Tamoxifen Resistance Identified

Researchers at Duke Comprehensive Cancer Center have identified a protein that breast cancer tumors overproduce when they become resistant to tamoxifen.

Future studies will be able to determine if tumors that overproduce this protein, called MTA-1, could be treated with a different hormonal therapy following their initial treatment with surgery, chemotherapy, and/or radiation, said Kimberly Blackwell, MD, Assistant Professor of Oncology, who presented the results at the San Antonio Breast Cancer Symposium.

Their findings support the research reported at the 2002 San Antonio meeting in which Dr. Blackwell demonstrated that tamoxifen-resistant tumors actually change their cellular characteristics to become responsive to other types of drugs.

Elevated levels of MTA-1 represent one of these cellular changes in tumors that stop responding to tamoxifen, she explained in a news release.

“MTA-1 is just one of the proteins that play a role in tamoxifen resistance, but it is one important step toward helping us better target our therapies toward each woman's particular type of tumor. Theoretically, we could biopsy women at the time of diagnosis and select an alternative drug to tamoxifen if their tumors overexpress MTA-1.”

MTA-1 is known to be a predictor of poor prognosis and the potential for breast cancer metastasis, so that testing for its presence prior to treatment could make it possible to devise more aggressive strategies from the outset, Dr. Blackwell continued.

Her research team developed a strain of mice whose tumors eventually became resistant to tamoxifen. Once tamoxifen resistance was achieved, Dr. Blackwell and her colleagues conducted a gene array analysis to determine which genes were overexpressed in the new tumor line.

They identified 20 different such genes, and found that MTA-1 was a gene that was strongly overexpressed in the tamoxifen-resistant tumors.

Figure. Kimberly Bla...
Figure. Kimberly Bla...
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To date, only a few other genes or proteins have been found to be overexpressed in tamoxifen-resistant tumors, the news release noted.

“We have a multitude of hormonally based drugs at our disposal that are designed to treat or prevent breast cancer and its recurrence,” Dr. Blackwell said. “Our ultimate goal is to test tumors at the time of diagnosis to determine what their molecular signatures are and then to select the best therapy aimed at treating the tumor.”

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▪ Origin of Myeloma Found in Stem Cell

Johns Hopkins Kimmel Cancer Center scientists have identified the cell likely to be responsible for the development of multiple myeloma. The research, published in Blood online, suggests that therapies designed for long-term cure should target this stem cell, which, unlike other cells, can copy itself and differentiate into one or more specialized cell types.

In investigating why myeloma so often recurs following drug therapy, the investigators uncovered a rare stem cell, occurring in just one out of every 10,000 cells, or less than 1% of all myeloma cells.

Working with immune system B-cells, the researchers found that this stem cell gives rise to the malignant bone marrow plasma cells characterized by multiple myeloma.

Current treatments target the malignant plasma cells but may not be effective on the errant multiple myeloma stem cells, allowing the cancer to recur.

“Most therapies today are aimed at the cancer you can see, but to cure cancer you have to go after the cells responsible for the disease, similar to how we kill a weed by getting at its roots, not just the part above the ground,” Richard Jones, MD, Professor and Director of Bone Marrow Transplant, explained in a news release.

“If you cut off the flower and stem of a dandelion, it may look like it has died for a period of time, but the weed eventually will grow back. If you get the root, however, the weed does not grow back.”

He and his colleagues found the rare stem cell by looking at markers on the surface of damaged B-cells, which develop into plasma cells that cannot divide and multiply.

As another member of the team, William Matsui, MD, elaborated, “We know what the markers are on cancerous plasma cells and the antibodies they make, and we also know the markers on B-cells that are not cancerous. So, we went looking for a B-cell that has the same antibodies, that can make copies of itself, and that can mature into cancerous plasma cells.”

The team found that this multiple myeloma stem cell looks and acts genetically different from the plasma cell. “Because these two cells are biologically different, we may need two therapies—one to kill the plasma cells, or the visible part of the weed; and one to kill the root, the stem cells,” Dr. Matsui noted.

“Treatments that are directed at myeloma plasma cells are likely to produce visible results, but they will be temporary improvements unless we also target the myeloma stem cell.”

Therapies for myeloma undergoing study at Kimmel include antibodies that target the stem cells and drugs to make them age prematurely. The research was funded by the National Cancer Institute.

Other participants in the research were Carol Ann Huff, Qiuju Wang, Matthew T. Malehorn, James Barber, Yvette Tanhehco, B. Douglas Smith, and Curt I. Civin.

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▪ Modified Poliovirus Used to Attack Brain Cancer

The cancer-killing properties of poliovirus were combined with a harmless genetic coding element from the common cold to fight brain cancers, in research reported by a team from Duke Comprehensive Cancer Center.

The resulting modified virus created a remarkably strong anticancer agent that rapidly killed cancer cells in laboratory cell cultures and in animals—and without causing polio, said Matthias Gromeier, MD, Assistant Professor of Molecular Genetics and Microbiology.

Testing of the new viral agent in humans should begin within two years, he said in a news release.

In the study, the modified poliovirus rapidly killed cancer cells derived from primary brain tumors as well as cells derived from breast and colon cancer metastases—all within a matter of four to six hours. In fact, polio is known to be one of the quickest killers of infected host cells, producing approximately 1,000 additional infectious viral units per infected cell, he added.

We made a drug out of a virus by engineering its destructive abilities from a foe into a friend.

His most recent results—a collaborative effort with Darrell Bigner, MD, Henry Friedman, MD, Allan Friedman, MD, and John Sampson, MD, of the Brain Tumor Center at Duke—were published in the December 9 issue of Proceedings of the National Academy of Sciences.

The key to the success was disabling the poliovirus' ability to kill normal brain cells while retaining its ability to kill cancer cells in the brain, Dr. Gromeier said.

To do so, the team swapped a critical genetic element from the common cold rhinovirus with the corresponding genetic element from the poliovirus. The genetic element, called an IRES (internal ribosomal entry site), enables a virus to express its own genetic information inside the host cell it has invaded.

Dr. Gromeier said he selected the IRES from a rhinovirus because it does not typically infect the human brain. Normal brain cells lack the appropriate environment required for the rhinovirus IRES to begin translating the poliovirus's genetic information, the study demonstrated.

“In cancer cells, the IRES from rhinovirus acts as the trigger that activates gene expression, but the genes being expressed—the silver bullets in the gun, so to speak—are all from the poliovirus,” Dr. Gromeier said. “The polio proteins kill the cancer cells quickly and efficiently.”

Polio is the perfect virus to attack brain cancer cells because it has a natural affinity for invading the brain, he continued. Polio infects brain cells by binding to a receptor or “docking site” called CD155 on the outside of motor neurons.

Dr. Gromeier and his colleagues showed that brain tumors overproduce this CD155 receptor, making the cancer cells particularly vulnerable to infection with poliovirus.

The modified poliovirus still enters normal motor neurons because it shares the same CD155 receptor as brain tumor cells, but it can no longer grow in normal cells.

“We have a virus that naturally targets brain cells, but we have replaced the genetic coding element that makes the virus so dangerous,” he said. “The virus has lost its ability to grow in normal neurons.”

Tests in mice and in non-human primates have confirmed that the modified poliovirus does, indeed, kill brain tumor cells but does not affect normal motor neurons. Moreover, viruses don't carry the toxic side effects of chemotherapy and radiation, and viruses can be introduced directly into the tumor.

The research was funded by the NIH, NCI, the Burroughs Wellcome Fund, the ABC2 Foundation, and the Brain Tumor Society.

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▪ High-Risk Melanoma: Disappointing Results for Low-Dose Interferon

A Phase III study examining the use of low-dose interferon following surgery in patients with high-risk melanoma showed no significant difference in recurrence-free or overall survival compared with patients receiving no further treatment.

The authors of the study, published online ahead of print on December 9 in the Journal of Clinical Oncology, concluded that after more than a decade of conflicting studies on adjuvant interferon use, patients and physicians should know the facts about interferon before pursuing treatment options for high-risk melanoma.

“Our study found no clear advantage of low-dose interferon therapy following surgery in high-risk melanoma patients,” said lead author Barry Hancock, MD, Professor in the Academic Unit of Clinical Oncology at the University of Sheffield in the UK.

The trial was initiated, he explained, after a series of studies on adjuvant interferon produced conflicting results and, in turn, conflicting interpretations of these results in both Europe and the US. In Europe, prolonged duration of low-dose interferon is often considered standard therapy, while in the US high-dose interferon is more commonly administered.

However, despite studies showing high-dose interferon to be effective in extending disease-free survival, there has been widespread concern, even in the US, among physicians and patients who believe the treatment to be ineffective or too toxic. As a result, researchers wanted to see whether prolonged, low doses of the drug would be effective in extending survival, without the harmful side effects of high-dose interferon.

Of the 674 patients enrolled in the trial, 338 received interferon following surgery, and 336 received no follow-up treatment. After five years, 63% of patients in both groups experienced disease recurrence (211 of the interferon-treated patients vs 215 of the controls), and 46% of patients in both groups died (151 for the interferon-treated patients vs 156 of the controls).

Five-year overall and recurrence-free survival were the same in both groups—estimated to be 44% and 32%, respectively.

In addition, the analysis found no clear difference in overall or recurrence-free survival when patients were compared by disease stage, age, and gender. As the researchers expected, low-dose interferon was relatively well tolerated, with fatigue and mood disturbance as the primary side effects.

“The debate on adjuvant interferon in high-risk melanoma continues. After many years of clinical research, there is good evidence that high-dose interferon improves recurrence-free survival, but no clear evidence of the benefit to overall survival,“ Dr. Hancock said in a news release. “Physicians and patients should be armed with all the facts so that they can make informed decisions regarding treatment.”

Two accompanying editorials appeared in the journal to discuss the debate. The authors noted that although the study did not find low-dose interferon to be a promising treatment for high-risk melanoma, it does provide insight into the available treatment options and implications for the design of future clinical trials.

“This study confirms that optimal care for patients with high-risk melanoma is still not clear,” said Lynn Schuchter, MD, Associate Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania.

As a result, treatment decisions will require the integration of existing evidence, judgment of experienced clinicians, and informed input from patients. Continued participation by physicians and patients in well-designed randomized clinical trials will facilitate continued progress in the treatment of melanoma.

“The challenge now is to go beyond these results—to develop more innovative and efficient clinical trials, and better identify those patients at risk of recurrence based upon the use of molecular genetic factors.”

© 2004 Lippincott Williams & Wilkins, Inc.

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