Promising New Research in Pediatrics Under Way

 

(From left:) Drs. Mark Roberts, Theodore Zipf, Eugenie Kleinerman and Francis Ali-Osman (seated) are conducting research that one day may translate into promising new therapies and help pediatric

cancer patients like Kalani Thomas.

 

For children with cancer, the promise of a bright future continues to get better. Thanks to significant advances in pediatric research and the development of new and improved therapies, more children are surviving cancer than ever before.

 

Just knowing that research has contributed to the estimated 80 percent pediatric survival rate is fuel enough for M. D. Anderson's Division of Pediatrics to continue pursuing a number of research initiatives.

 

"We have the potential to find solutions and improve pediatric cancer survival," says Dr. W. Archie Bleyer, head of the Division of Pediatrics. "Because cancer is all we do and it is the sole mission of everyone here from nurses to basic researchers to physicians, we have the resources and support to fight for those 20 percent of children who will not survive their disease."

 

While there is a wide variety of encouraging research under way at M. D. Anderson in most pediatric cancers, there are three particularly promising new areas of research involving acute lymphoblastic leukemia (ALL), osteosarcoma and resistance to chemotherapy, Dr. Bleyer says.

 

Acute Lymphoblastic Leukemia

An M. D. Anderson study published last winter in the New England Journal of Medicine opened new doors to a better understanding of acute lymphoblastic leukemia (ALL) in children.

 

The study, led by Drs. Theodore Zipf and Mark Roberts, not only refuted a 30-year-old dogma universally held by the medical community, but also began a new generation of research into predicting relapse, determining how chemotherapy works and how it changes cells, and determining what role the immune system has in fighting the disease.

 

Using two sensitive molecular assays, the research team found that up to thousands of leukemia cells may remain in a patient long after successful treatment. The presence of such cells, however, does not necessarily mean that the patient will relapse into ALL.

 

"These findings have brought pediatric leukemia research into a whole new light," says Dr. Zipf, chief of pediatric leukemia and lymphoma. "We now know that it is not necessary to kill every leukemia cell with chemotherapy to have a successful outcome. We previously believed that the leukemia had to be eradicated to achieve cure, but we now see that this is not necessary. With the capability to obtain new information such as this, we can now learn more about how chemotherapy cures leukemia."

 

Drs. Zipf and Roberts hope that the research ultimately will lead to a test that can predict relapse of ALL. Should a test be developed, new therapies could follow or existing treatments could be altered to respond more effectively - and earlier - to possible relapse.

 

"Though we are far from developing a test, we could improve our cure rate if we could test for relapse, then treat accordingly," says Dr. Roberts, associate professor of pediatrics. "By predicting relapse, we could tailor risk-directed therapies to patients who face relapse or possibly look for a milder form of therapy for those who are not going to relapse."

 

Such developments in future decades could help improve the 75 percent cure rate for ALL, particularly among those patients who relapse. Of the 25 percent who do not survive, most die as a result of their disease recurring. Currently, 10 to 20 percent of children who relapse survive.

 

 

Osteosarcoma

In the last decade, the 65 percent survival rate in pediatric osteosarcoma has been stagnant and, for that reason, Dr. Eugenie Kleinerman has been striving to make a difference for the future.

 

Dr. Kleinerman's research seeks to prevent lung metastasis in osteosarcoma patients, a grave condition which occurs in about 80 percent of children with this type of bone cancer. In most cases, children who die from this disease fail to survive because the disease moves to the respiratory system.

 

Dr. Kleinerman is testing a new biological agent, to be used in conjunction with chemotherapy, that stimulates the body's own immune system and wipes out the disease while leaving normal cells intact. She believes that using the two therapies together will improve the cure rate. Chemotherapy and surgery will eliminate the bulk disease in the bone, while the immunotherapy can hopefully kill the drug-resistant cells left behind in the lung, says Dr. Kleinerman, professor of cell biology and clinical pediatrics.

 

Currently in Phase III trials at 250 institutions throughout the United States, the agent known as MTP-PE stimulates cells to activate genes that invigorate the immune system. Wrapped in a fatty coating no larger than a red blood cell, the MTP-PE is given intravenously to patients in a saline solution.

 

The MTP-PE study is scheduled to close at the end of this year and will take another year to compile data.

 

"What we have seen with the agent so far is very promising," Dr. Kleinerman says. "We believe that if results are good with osteosarcoma, we may be able to try this with other cancers that often spread to the lungs, such as renal cell carcinoma, Ewing's sarcoma and Wilms' tumor."

 

 

Resistance to Chemotherapy

For the last 15 years, Dr. Francis Ali-Osman has been persistent in his quest to find out why most pediatric and adult patients develop a resistance to chemotherapy at some time in their treatment.

 

While some patients develop a resistance after a few months of chemotherapy, there are some patients who are resistant to therapy at the time of diagnosis, says Dr. Ali-Osman, chairman of the Department of Experimental Pediatrics. Of the 20 percent of pediatric patients who die, most develop a resistance to chemotherapy, a primary treatment for many pediatric and adult cancers.

 

Though each patient's level of resistance is different, Dr. Ali-Osman believes it can be triggered by the same mechanism, namely the overexpression of a gene encoding the glutathione S-transferase (GST) protein. He recently reported the discovery of two novel forms of the GST gene present in lymphomas and tumors of the brain, breast and colon.

 

Dr. Ali-Osman's work has shown that the product of this gene not only has the ability to "detoxify" the chemotherapy agents but also is involved in the "repair" of the damage produced by the chemotherapy in cancer cells.

 

If ongoing studies prove successful, Dr. Ali-Osman hopes that within two years clinical trials could begin on agents that will not only break down tumor defense mechanisms against anticancer agents but also protect normal cells from the toxic side effects of chemotherapy.

 

Patients in the trial would be given the "anti-gene" agent, antisense oligonucleotide, that blocks expression of the GST genes in advance of their chemotherapy regimen. Given prior to the treatment, the antisense agent would block the activity of the GST genes in the tumor cells and thereby reduce or overcome their resistance to chemotherapy.

 

According to Dr. Ali-Osman, such a trial could have far-reaching effects in the coming years. "Research gathered from this trial would allow us to improve a patient's chance for response and help us learn more about the possibilities for this type of gene therapy as a treatment modality," he says.

 

"Chemotherapy is a standard treatment for so many cancers that we could make some major inroads to improving survival rates in colon, lung and ovarian cancers in adults, and some types of leukemia and brain cancers in children," Dr. Ali-Osman adds. "Though we are still a few years from this, we are very excited and encouraged by what we have seen so far."

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