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Sensitivity can be considered good or bad, depending on the situation. If a doctor is described as sensitive, that’s a positive attribute. If a prizefighter is stuck with the label, it’s not so good. But when it comes to the treatment of a rare form of acute lymphoblastic leukemia (ALL), researchers at St. Jude Children’s Research Hospital are on the verge of delivering a knockout punch. They are studying a way to make ALL cells sensitive to an effective treatment to which they were becoming resistant.
Now that’s a form of sensitivity even a heavyweight contender can celebrate.
When St. Jude opened its doors in 1962, the survival rate for pediatric ALL was a dismal 4 percent. Today, 94 percent of newly diagnosed ALL patients can expect to be long-term survivors. ALL is the most common form of childhood cancer. Approximately 12,500 children will be diagnosed with cancer each year, and of this number a whopping 30 percent will receive a diagnosis of ALL.
However, within this group of 30 percent is a small subset of patients with an extremely rare and devastating form of leukemia known as Philadelphia chromosome-positive ALL (Ph+ ALL). Less than 5 percent of the total pediatric leukemia population has this form of the disease, and their prognosis is still poor.
Preparing for the fight
This rare subset of leukemia occurs when two chromosomes fuse to form an oncogene (a cancer-stimulating gene) called the BCR-ABL kinase. BCR-ABL sets off a cascade of signals that drive ALL cells to divide rapidly, resulting in cancer formation. However, in order for things to reach that point, the BCR-ABL kinase must bob and weave to avoid the body’s natural defense mechanisms, such as tumor suppressor genes. These cancer-combating genes recognize when a cell is responding to abnormal signals and cause the affected cells to commit suicide, thus knocking the cancer out cold.
Charles Sherr, MD, PhD, co-chair of Genetics and Tumor Cell Biology and a Howard Hughes Medical Institute investigator, has studied such tumor suppressor genes for a number of years. One such gene, ARF, would normally take out the BCR-ABL enzyme with one punch. But ARF is frequently absent in patients with Ph+ ALL. Sherr and his colleagues, Richard Williams, MD, PhD, of St. Jude Oncology, and Martine Roussel, PhD, of Genetics and Tumor Cell Biology, have carefully examined how ARF loss speeds ALL progression.
One drug that has shown promise in the fight against this rare form of ALL is imatinib, also known as Gleevec©. This drug blocks BCR-ABL’s ability to signal cells to divide rapidly. But laboratory models of Ph+ ALL established by these investigators revealed that removal of the ARF gene greatly enhances the aggressiveness of BCR-ABL-induced ALL and contributes to imatinib resistance.
Thus, determining an effective treatment for Ph+ ALL isn’t as simple as delivering a one-two punch. The researchers also discovered that leukemia cells that had not responded to imatinib therapy still displayed sensitivity to the drug.
“Paradoxically, the resistance is not due to a change in the tumor cells themselves but instead reflects an altered relationship between the tumor cells and the body,” Sherr says.
Delivering the K-O
So what is the secret to delivering a knockout treatment?
The critical issue is to determine the basis of the imatinib resistance.
According to Sherr and Williams, inactivating ARF enables ALL cells to thrive in the bone marrow even when the cancer-stimulating signals from BCR-ABL are blocked by imatinib. Thus, finding drugs that work hand in hand with imatinib to limit survival of the tumor cells should prove effective in treating this rare form of ALL.
“When children have this disease, it’s very aggressive, and they generally don’t respond as well to conventional treatment,” Williams says. “Tragically, some of these children still die, despite receiving the maximum therapy available.”
One of the unique aspects of this research is its scope. While Ph+ ALL is rare in children, it accounts for about one-third of adult ALL cases, with an equally poor prognosis. This is in stark contrast to chronic myelogenous leukemia (CML), a disease also caused by the BCR-ABL kinase. In CML, where the ARF gene is intact, imatinib therapy is remarkably successful in keeping almost all patients in long-term remission; infrequent drug resistance that develops is usually due to acquired mutations of the BCR-ABL oncogene within the leukemia cells.
Scientists’ ultimate, long-term goal is to use the genetics of these leukemias to target their treatment. “Although it is ambitious to think about putting ARF back into the cells,” Williams says, “our efforts have already given us an enhanced understanding that is bringing us closer to developing effective treatments to fight these leukemias.”
With these insights comes the hope of winning the final round against cancer and knocking it out for good.
Reprinted from Promise magazine, winter 2007.