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Tom Swartz

Gene Silencing Inhibits Tumors in Ewing's Sarcoma Model

Scientists have used a new method of silencing genes to inhibit Ewing’s sarcoma in mice.  The findings were presented on April 19th at the annual meeting of the American Association for Cancer Research (AACR).  Ewing's sarcoma has been traced to two chromosomes that break and exchange genetic material, activating a gene called EWS-FLI1 that is critical to the development of the tumors. Silencing the gene, however, can inhibit Ewing's tumors. The potential of gene silencing approaches in blocking the activity of genes involved in cancer has been suggested by many studies in cell cultures. In this study, scientists from Childrens Hospital Los Angeles and the California Institute of Technology developed a delivery method using a short interfering RNA (siRNA) molecule designed to silence the gene EWS-FLI1. The siRNA was packaged with sugar-containing polymers and delivered into tumor cells by a modified protein called transferrin that normally ferries iron into cells.  The scientists set out to design a delivery system that could work systemically in metastatic disease. When the treatment was given over 4 weeks, the results were "striking" and the tumor growth effectively stopped in many animals, according to Dr. Hu, a postdoctoral fellow at Children's Hospital Los Angeles and the University of Southern California, who presented the research at AACR. The ultimate goal is to modify the method for use in people, as an intravenously administered treatment. The sugar molecules, or cyclodextrins, in the polymer that packages the siRNA have been used in pharmaceuticals and are nontoxic, and don’t cause an immune response. Dr. John Rossi of the Beckman Research Institute in Duarte, Calif. commented that this new method "is a real breakthrough in systemic delivery of non-chemically modified siRNAs." While Dr. John Mendelsohn, president of the University of Texas M.D. Anderson Cancer Center, has said, "This is a lovely study that combined several technologies to silence a gene," and he predicted that the approach would eventually be tested in human clinical trials.

Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

Insulin-like growth factor-I receptor (IGF-IR) has been found to provide a major contribution to the malignant behavior of sarcomas.  In this study, the investigators analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR - NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma.  NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. The study found that Ewing's sarcoma cells were generally more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of Ewing’s to IGF-IR signaling. NVP-AEW541 induced a G(1) cell cycle block in all cells tested, whereas apoptosis (programmed cell death) was observed only in those cells that show a high level of sensitivity. In addition, concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, the investigators believe these results encourage the inclusion of this drug, especially in the treatment of patients with Ewing's sarcoma.  The investigators believe that for the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide

A small interfering RNA targeting vascular endothelial growth factor inhibits Ewing's sarcoma growth in a xenograft mouse model

Angiogenesis plays an essential role in tumor growth and metastasis and is a promising therapeutic target for cancer. Vascular endothelial growth factor (VEGF) is a key regulator in vasculogenesis as well as in angiogenesis. TC71 human Ewing's sarcoma cells overexpress VEGF, with a shift in isoform production from membrane-bound VEGF189 to the more soluble VEGF165. Transfection of TC71 cells with a vector-based VEGF targeted small interfering RNA expression system (VEGFsi) inhibited VEGF165 expression by 80% and VEGF165 protein production by 98%, with no alteration in VEGF189 expression. Human microvascular endothelial cell proliferation and migration induced by conditioned medium from VEGFsi-transfected TC71 cells was significantly less than that induced by conditioned medium from TC71 cells and control vector-transfected TC71 cells. Furthermore, after s.c. injection into athymic nu/nu mice, the tumor growth of VEGFsi-expressing TC71 cells was significantly less than that of parental or control vector-transfected cells. Vessel density as assessed by CD31 immunohistochemical analysis and VEGF165 expression as assessed by Northern blotting were also decreased. Intratumor gene therapy with polyethylenimine/VEGFsi also resulted in tumor growth suppression. When inoculated into the tibias of nude mice, VEGFsi-expressing TC71 cells induced osteolytic bone lesions that were less severe than those induced by control groups. These data suggest that targeting VEGF165 may provide a therapeutic option for Ewing's sarcoma.

Clinical Trial Participation Influences Cancer Outcomes

Getting more young adults with cancer to participate in clinical trials could lead to better survival rates. That is the finding of a new study out of M.D. Anderson Cancer Center in Houston involving survival rates and clinical trial participation among young adults with two forms of sarcoma.  The researchers explain that survival rates for children and older people suffering from sarcomas have improved markedly over the past quarter century, but survival rates for those between ages 15 and 45 have not kept pace. They looked at the impact clinical trial participation might be having on this outcome by comparing trial participation and outcomes between patients with non-Kaposi sarcoma and Kaposi’s sarcoma (KS). The latter form of the disease is most common in AIDS patients. Therefore, more young adults have been included in clinical trials on its treatment. Results showed younger adults with non-KS sarcomas had both the lowest level of clinical trial participation and the least improvement in mortality rates. By contrast, younger adults suffering from KS had higher clinical trial involvement and better survival rates.  The researchers note these results are similar to those seen in studies involving leukemia and other types of cancer and point to the need to improve clinical trial participation among young adults with cancer. Luckily, that’s now happening in sarcoma research, as several study groups have increased the age range of patients eligible for their clinical trials.

Diagnostic Imaging Update: Soft Tissue Sarcomas [You need to register (which is free) to get the article.]

No single imaging approach is ideal for every tumor. The imaging of soft tissue sarcomas requires a multimodality approach.  The authors of this article discuss the general imaging approaches for patients who present with soft tissue masses. It is not intended as a comprehensive review, but rather as an overview of MRI, CT, PET, ultrasound, and magnetic resonance angiography (MRA) techniques. It emphasizes the fundamental principles inherent to tumor imaging and the specific applications of the newer imaging modalities.  

Sarcoma Institute at Menorah Medical Center

The Sarcoma Institute at Menorah Medical Center, located in Overland Park, Kansas, is a multi-disciplinary team of physicians, nurses, and allied health professionals dedicated to the care and treatment of patients with bone and soft tissues tumors. From infants to seniors, the professionals of the Sarcoma Institute treat patients with both primary malignant and benign tumors of the bone and soft tissues, as well as metastatic cancer of the bone.  The Institute provides state-of-the-art treatments including surgical, medical and radiation, in a combined modality to offer patients the most effective care. Both research and education play a crucial role in the Institute by enhancing patient knowledge and continuing to enhance the field of sarcoma.

V2N3 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative.