In late September, a vocal throng of citizens assembled outside the Utah Capitol Building to protest against the states Division of Child and Family Services. Complaints about government agencies are hardly unusual, but what was striking about this rally was that it had been precipitated by Ewings sarcoma, a rare family of childhood cancers that seldom grabs the public spotlight.
At issue was whether 12-year-old Utah resident Parker Jensen, who has Ewings sarcoma, must receive chemotherapy to kill tumor cells that likely linger in his body. Officials with Utahs child services division had ordered 4 months earlier that he should be treated, standing behind clinical data and threats of stiff legal actions. Parkers parents were equally adamant that their son should receive a milder alternative therapy, reportedly fearing that the standard 11-month, 14-cycle chemotherapy regimen would stunt Parkers growth and leave him sterile.
For those who follow oncology, the dispute raised an intriguing question: Why dont Parkers parents have a third option: a cancer pill, like the breakthrough drug Gleevec, that in this case would directly and specifically target Ewings tumor cells, switching off their signal to grow and producing few, if any, serious side effects?
The question would be frivolous had not French scientists 11 years ago identified a protein that is unique to Ewings sarcoma and is present in about 95% of tumors, making it one of the most highly specific so-called molecular targets
in all of oncology. In fact, scientists say this abnormal proteina two-headed chimera of the proteins EWS and FLI1is growth-promoting in culture, and likely plays an important role in causing Ewings sarcoma.
Although researchers have this fantastic lead working in their favor, the process is not as easy as designing a drug, aiming it at the target, and throwing the whole thing into clinical trials. Researchers in the field say the broad cellular function of their target is so poorly understood that it would be reckless to blindly gear up for clinical trials. Moreover, even if all of the scientific bugs were worked out, the researchers say there is no financial incentive for industry to commercialize a drug that would have a market even smaller than that of the rare chronic myelogenous leukemia, the original condition targeted by Gleevec.
As a result, an exciting discovery that might lead to a cure for this potentially deadly cancer has hit a scientific and commercial impasse, leaving families like the Jensens to grapple with tough choices involving non-specific chemotherapy drugs that might or might not benefit their child.
Once Grave Prognosis
A generation ago, most of the approximately 500 Americans diagnosed each year with Ewings sarcoma faced virtual death sentences. Today, about two-thirds of Ewings sarcoma patients with localized tumors can beat the disease with radiation and high-dose chemotherapy, which often consists of alkylating agents that first were developed for other malignancies.
However, one-third of the above-mentioned patients still die from the cancer. And the prognosis is poor for the other roughly 25% of Ewings patients who present with metastatic or recurrent disease. Its that other third that we care a lot about, and we cant figure out why treatment is ineffective,
said Daniel C. West, M.D., a pediatric oncologist at the University of California at Davis in Sacramento.
For all that we can tell, they appear to be the same as those that we cure.
West said he and others remain concerned about the possible high price of cure.
As a study published in 1999 reported, of 31 young Ewings patients who were treated and
cured
during the 1970s and 1980s at a leading American cancer center, five later relapsed and seven developed secondary malignancies over the next two decades.
Given the risks and shortcomings of current treatment, the vast majority of pediatric oncologists do not hide their enthusiasm for an Ewings version of the Gleevec cancer pill. It would be fantastic,
said West.
The notion that you would take a pill for as long as needed to either complement the cytotoxic chemotherapy, prevent recurrences, or, in fact, replace some or all of the chemotherapy would be absolutely fantastic.
Mysterious Origin
Most pediatric oncologists, however, know from experience not to hold their breath. One reason is simply the confounding nature of Ewings sarcoma, a cancer that defies easy classification. In a field that defines malignancies based on their tissues of origin, Ewings has no obvious home base, arising about 85% of the time in bone, particularly long bones and pelvis, but it can also strike the soft tissues, including, in the case of Parker Jensen, the mouth. The malignancies, which pathologists describe as a soft, greyish, poorly differentiated tumor, offer no solid molecular clues to their origin, neither does Ewings run in families, meaning genetic studies yield nothing.
Because the cancer appears primarily in children and adolescentsthough adults do occasionally present with Ewings sarcomascientists agree it is a developmental tumor that is triggered at some point during childhood. What they do not know is in which embryonic layer the tumor is seeded. James Ewing, the legendary cancer pathologist who first discovered the malignancy more than 80 years ago, described his find as an endothelioma of bone,
which would peg it to the bone-generating mesoderm. But the tumor expresses neural proteins that suggest it is derived from the ectoderm.
Youre left with this quandary,
noted Christopher Denny, M.D., a Ewings researcher at the University of California at Los Angeles.
Is it neuroectodermal? Is it mesodermal? Or, is it some sort of cell of origin that can have both differentiative capacities?
Also dampening the enthusiasm for an easy treatment is the scientifically murky function of their molecular target. This chimeric proteinthe abnormal fusion product of the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11likely functions as a transcription factor, the complex group of proteins that control gene expression. Scientists suspect that the abnormal EWS/FLI1 protein, in tandem possibly with other proteins, triggers the incorrect and/or mistimed expression of genes in certain developing tissues.
|
Assuming the drug gets there, they also know little about how precisely to strike their target. A transcription factor tends to be rather modular, meaning it has different parts that do different things,
said Joseph Bidwell, Ph.D., who studies transcription factors at the Indiana University Medical Center in Indianapolis.
It has a part that binds to DNA, a part that will activate or repress transcription, and possibly another part that interacts with other proteins to form complexes.
As scientists note, at which arm of this modular protein does one aim to silence it? And, if a compound shuts down all of the arms in the process, could this induce unwanted effects? In the case of EWS/FLI1, which scientists suspect activates a specific sequence of presently unknown genes, it could have serious implications. Although an inhibitor might switch off a gene that helps give rise to a Ewings tumor, it could inactivate other genes in the sequence that are vital to health. Or, by turning off some of these genes, the inhibitor may induce other unwanted developmental conditions.
Adding to the uncertainty is the fact that in their normal state, both EWS and FLI1 are necessary transcription factors. Suzanne Baker, Ph.D., a scientist at St. Jude Childrens Research Hospital in Memphis, Tenn., said that if a small molecule aimed at the Ewings chimera veered off course and began sticking to normal copies of EWS, FLI1, or their relatives, it could wreak molecular havoc. For instance, FLI1 belongs to the etch family of genes, of which there are more than 30 members, each of which attach to the same signature DNA sequence. Thus, if a compound were synthesized to block the FLI1 portion of the chimera from binding to its signature sequence, it hypothetically could switch off 30 genes at once.
|
Worth the Effort?
Despite these caveats, scientists who study Ewings sarcoma say an EWS/FLI1 inhibitor is well worth pursuing just for the scientific reasons alone. First and foremost, the researchers say Ewings is one of the few tumors in which scientists have identified a unique and nearly omnipresent molecule that fuels its abnormal growth. Weve got a great target, one that the tumor absolutely needs,
said Denny.
Olivier Delattre, M.D., Ph.D., a scientist at the Institut Curie in Paris and whose laboratory discovered the EWS/FLI1 fusion protein in the early 1990s, said Ewings sarcoma is one of the best models to explore transcription regulation and cancer. Based on genetic analyses, including karyotyping, additional oncogenic events [mutations] may not be very numerous in Ewings,
he noted.
Therefore, EWS-FLI1 is probably the major oncogenic event, and it is probably one of the most frequent cancers with a major genetic event involving a transcription factor.
This is a great model to study how chimeric transcription factors work,
said Denny.
We all sort of have an idea of how they work, but there must be at least 40 or 50 of them involved in various leukemias and solid tumors. The more we learn about these things, the more themes that we will pick up and cross fertilize different fields.
Denny and others say one of their greatest challenges of all will be to interest funding agencies and/or pharmaceutical companies to invest in the research.
Ewings researchers note that pharmaceutical companies have no financial incentive to commercialize this hypothetical miracle drug; the market is far too small to profit companies and shareholders, which, in turn, serves as a disincentive for NIH and other funding agencies to move heaven and earth to develop a high-risk compound that could end up on a shelf.
This catch-22 raises an issue that some predict will increasingly confront industry in the coming age of molecular medicine. As scientists define breast cancer, lung cancer, prostate cancer, and other cancers as not one but hundreds of distinct molecular entities, how will industry cope with developing drugs for what amount to a series of small market conditions? Some say the answer may be for academia to make high-risk, cross-cutting scientific opportunities, such as transcription inhibitors, a greater funding priority, and for dialogue to commence on how to ensure that the highly targeted orphan drugs of the future do not end up as victims of the marketplace.
In the meantime, researchers who study Ewings continue to plug away in the laboratory and hope that one day families like the Jensens will have even better choices to make to beat this potentially deadly cancer.
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |