New Treatment for Ewings Sarcoma Type Bone Cancer, Showing Hope

New Treatment for Ewings Sarcoma Type Bone Cancer, Showing Hope

Sarcomas are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm. The various sarcomas include bone sarcomas (osteosarcomas and chondrosarcomas), Ewing’s sarcomas, peripheral primitive neuroectodermal tumors, and soft tissue sarcomas, which are the most frequent.

In 1921, James Ewing, MD, described a bone tumor that, unlike the common bone tumor, osteosarcoma, could be treated with radiation. This newly identified tumor became known as Ewing’s tumor. At first, this tumor was only seen in bones. Soon, the same type of tumor was detected in the soft tissues and named extraosseous Ewing’s (EOE).A tumor is described by size, where it originated, and whether it has spread. This is called staging. A tumor of the Ewing’s family (TEF) is staged as either localized (involving only the site of origin and nearby tissues) or metastatic (involving spread to distant parts of the body).

Ewing's sarcoma can occur any time during childhood, but usually develops during puberty, when bones are growing rapidly. It is uncommon in African-American, African, and Chinese children.The tumor may arise anywhere in the body, usually in the long bones of the arms and legs, the pelvis, or the chest. It may also develop in the skull or the flat bones of the trunk.

Ewing's sarcoma can occur in any bone, but is most often found in the extremities and can involve muscle and the soft tissues around the tumor site. Ewing's sarcoma cells can also spread (metastasize) to other areas of the body, including the bone marrow, lungs, kidneys, heart, adrenal gland, and other soft tissues. This type of bone tumor accounts for nearly 30 percent of pediatric bone cancers.

Ewing's sarcoma has a tendency to metastasize rapidly. Treatment may involve chemotherapy with multiple drugs as well as radiation therapy and surgery to remove the primary tumor.Ewing's sarcoma share common risk factors and side effects from treatment. Chances for recovery depend upon where the tumor is located, its size, and whether it has spread. But both types of bone cancer respond well to treatment and are curable in many cases.

There are few symptoms. The most common is pain and occasionally swelling at the site of the tumor. Children may also break a bone at the site of the tumor after a seemingly minor injury (this is called a "pathologic fracture"). Fever may also be present.Comparative molecular analyses of primary Ewing’s sarcomas and their apparent metastatic osseous counterparts are warranted and may lead to further insights into the pathogenesis of this rare cancer.

Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly, metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system and lymph nodes.Survival for localized disease is 65-70% when treated with chemotherapy. Long term survival for metastatic disease can be less than 10% but some sources state it is 25-30%

Soft tissue sarcoma (STS) such as Ewing sarcoma/primitive neuroectodermal tumors (PNET), myxoid/round cell liposarcoma, alveolar rhabdomyosarcoma, malignant melanoma of soft tissues/clear cell sarcomas, desmoplastic small round cell tumor, and synovial sarcoma all can have distinctive cytogenetic alterations whose presence may have treatment and prognosis implications.

Specific inherited genetic alterations are associated with an increased risk of both bone and soft tissue sarcomas. The oncogenes (ie, genes that can induce malignant transformation and tend to drive cells toward proliferation) that have been implicated in the development of soft tissue sarcomas include MDM2, N-myc, c-erbB2, and members of the ras family. Amplification of these genes in several subtypes of soft tissue sarcomas has been shown to correlate with an adverse outcome. The best characterized gene rearrangements have been found in Ewing’s sarcoma (EWS–FLI-1 fusion), clear-cell sarcoma (EWS–ATF1 fusion), myxoid liposarcoma (TLS–CHOP fusion), alveolar rhabdomyosarcoma (PAX3–FHKR fusion), desmoplastic small round-cell tumor (EWS–WT1 fusion), and synovial sarcoma (SSX–SYT fusion).

The proper planning of the biopsy procedure is extremely important and should only be performed by orthopedists experienced in the care of children with malignant bone tumors. If Ewing's sarcoma is not treated with chemotherapy, more than 90 percent of patients will develop widespread disease most often in the lungs, other bones and bone marrow. A combined approach with surgery, radiation therapy and chemotherapy has improved the chance for cure for these children.

Scientists studying Ewing's sarcoma and developed a new drug called MIG-B that attaches a radiolabel to a unique substance of the neuroblastoma tumor to destroy it. Ewing's sarcoma bears some similarities to neuroblastoma, and, following MIG-B as a model, our sarcoma investigators are working in partnership with scientists from The Johns Hopkins University to develop a similar drug for testing.

A study from scientists at the University of Freiburg, Germany, and their collaborators at the National Cancer Institute (NCI), part of the National Institutes of Health, has pinpointed a potential mechanism for resistance of Ewing’s sarcoma, a type of bone cancer, to a protein that may be useful in fighting cancer — and a possible method for overcoming this resistance.

The protein, called TRAIL (tumor necrosis factor apoptosis-inducing ligand),has generated tremendous interest among scientists looking for new therapies that target cancer cells but spare normal dividing cells. TRAIL binds to receptors on the surface of cancer cells and sets off a series of signals that cause the cells to commit suicide. Almost all normal cells are unaffected by TRAIL. The cells of many solid tumors, including Ewing’s sarcoma, have shown extreme sensitivity to TRAIL in laboratory experiments, and investigators have started testing the protein in early clinical trials.

Ewing’s sarcoma is the second most common bone tumor in children and adolescents. For children who have metastatic or relapsed disease, their prognosis is poor. More effective treatments are needed for these patients.

The scientists who conducted the study, led by Udo Kontny, M.D. from the University of Freiburg, showed that Ewing’s sarcoma cells that express low levels of an enzyme called caspase-8, which plays a role in cell suicide (apoptosis), are resistant to TRAIL-induced killing. However, the addition of interferon-gamma, a protein produced by cells of the immune system, to treatment with TRAIL caused the resistant cells to produce more caspase-8, making them once again sensitive to TRAIL-induced death.

“This study is an excellent example of how modern molecular biology can help us unlock the detailed mechanisms driving the new, targeted therapies for cancer,” said NCI Director John E. Niederhuber, M.D. “If a targeted treatment that shows promise in the laboratory does not work as expected in clinical trials, we need to go back and understand what properties of the cancer cells might be driving resistance.”

“When you look in the test tube, it’s really quite remarkable how quickly and dramatically Ewing’s sarcoma is killed by TRAIL,” explained Crystal Mackall, M.D., from NCI’s Center for Cancer Research (CCR), whose laboratory headed the NCI portion of the investigation. “But the initial results in animal studies were just not as effective as we would have expected. So we ended up thinking that, however this tumor is becoming resistant, it must be really important, and we’re going to need to add something to improve the effectiveness of TRAIL treatment in the clinic.”

The scientists focused on caspase-8 because lack of the protein had been linked in laboratory studies to TRAIL resistance in Ewing’s sarcoma cells and the cells of other tumors. To see if caspase-8 expression is also limited in tumor tissues acquired from patients, the researchers measured the expression of caspase-8 in 54 tissue samples taken from 47 patients with Ewing’s sarcoma. They found that, while 50 out of the 54 samples expressed caspase-8, the number of cells within each sample that expressed the protein varied considerably. In 76 percent of the samples, caspase-8 expression was detected in 60 to 100 percent of the cells. In the other 24 percent of the samples, caspase-8 expression was detected in only 0 to 50 percent of the cells. Therefore, within any individual Ewing’’s sarcoma tumor, cells that lack caspase-8 could cause resistance to TRAIL.

The investigators next tested whether interferon-gamma, which has been shown in the laboratory to increase caspase-8 expression in cells, could sensitize Ewings’s sarcoma cells with low expression of caspase-8 to treatment with TRAIL. They found that doses of interferon-gamma, within the range easily tolerated by patients, increased caspase-8 expression in caspase-8-deficient cells. When the interferon-gamma-treated cells were treated with TRAIL, they underwent cell death, indicating restored sensitivity to TRAIL.

Because most patients with Ewing’s sarcoma undergo chemotherapy, the investigators also looked at whether chemotherapy alters the levels of caspase-8 in Ewing’s sarcoma tumors. Using samples from the same 47 patients, they compared the number of tumor cells expressing caspase-8 between tumor samples collected before and after chemotherapy. They did not find any significant difference between the samples, suggesting that chemotherapy does not select for tumor cells that lack caspase-8, which would make subsequent treatment with TRAIL less effective. Data indicated that caspase-8 does not influence the sensitivity of Ewing’s sarcoma tumors to chemotherapy.

The investigators confirmed these results in the laboratory. When cells with different levels of caspase-8 expression were treated with the chemotherapy drug doxorubicin, no differences in sensitivity to the drug were seen. Changing the levels of caspase-8 expressed by the cells, genetically or by adding interferon-gamma, did not alter their sensitivity to chemotherapy, indicating “that the combination of TRAIL and interferon-gamma with standard chemotherapeutics in Ewing’s sarcoma could be feasible,” stated the authors.

“I’d like to see a clinical trial in humans of interferon-gamma and TRAIL or an agent that interacts with the TRAIL receptor, because I do believe that adding interferon-gamma will make cells more susceptible to TRAIL-induced killing,” said Dr. Mackall. An early phase study will be particularly important, she explained, because it is possible that adding interferon-gamma to treatment with TRAIL might also increase the incidence of side effects.


Will there be a clinical

Will there be a clinical trial, if so I would love to be in it. I have recurrent ewing's sarcoma and things arrant looking good.

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