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Our Clinical Trials Continually updated listing of our clinical trials for soft tissue sarcomas
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Soft tissue sarcoma is a family of rare tumors that can occur anywhere in the soft tissues of the body -- fat, muscle, connective tissue, and nerves. Our clinical research team includes medical and radiation oncologists, pathologists, radiologists, and surgeons. We have developed the world's largest prospective database of sarcoma patients, which now contains data, starting from 1982, on more than 6,000 Memorial Sloan-Kettering patients who have received inpatient treatment.
Our team has pioneered many advances in the treatment of soft tissue sarcoma, new chemotherapies, new methods of radiation therapy (such as brachytherapy), and new surgical techniques to spare healthy tissue. Currently, members of our team contribute approximately half of all the articles for publication worldwide on soft tissue sarcoma research.
Among our recent research accomplishments:
Detection, Diagnosis, and Prognosis
- We found that synovial sarcomas, round-cell/myxoid liposarcomas, clear-cell sarcomas, and gastrointestinal stromal tumors (GIST) display remarkably distinct and homogenous gene expression profiles, and that a subset of malignant fibrous histiocytomas -- a controversial histological subtype -- is a distinct genomic group.
- Our progress in understanding the pathobiology of the soft tissue sarcomas and the relation of genetic change to clinical behavior has been impressive. Our investigators have cloned two novel sarcoma translocations: the ASPL-TFE3 fusion of alveolar soft-part sarcoma and the EWS-CREB1 fusion seen in a subset of clear-cell sarcomas. This achievement has led directly to the introduction into routine clinical use of molecular assays for the ASPL-TFE3 fusion, along with several other chimeric fusion gene products (ASPL-TFE3, EWS-FLI1, SYT-SSX, and PAX-FKHR). Clin Cancer Res. 2006;12:5356-5362. [PubMed Abstract]
- Our focused studies of specific genes or loci have revealed the apparently dramatic prognostic impact of p53 and p16/CDKN2A alterations in soft tissue and skeletal Ewing's sarcoma; these findings are being validated prospectively by the Children's Oncology Group and by the European Intergroup Cooperative Ewing's Sarcoma Study. Memorial Sloan-Kettering investigators have identified prognostic factors for local and distant recurrence, identified high-risk groups and evaluated outcome by site and histopathology, confirmed the prognostic impact and histological correlates of the SYT-SSX fusion type in a large multi-institutional series of patients with synovial sarcoma, and developed a sarcoma-specific nomogram to predict disease-specific survival over 12 years of follow-up, as well as a liposarcoma-specific prognostic nomogram. Using the Affymetrix expression chip platform, we have studied adult soft tissue sarcoma and have mined these microarray datasets for potential immunotherapy targets. J Clin Oncol. 2005;23:548-558. [PubMed Abstract]; Ann Surg. 2006;244:381-391. [PubMed Abstract]; Cancer Immun. 2005;5:2. [PubMed Abstract]
Novel Therapeutic Approaches
- We are leading an intergroup effort (American College of Surgeons Oncology Group), with strong Memorial Sloan-Kettering translational involvement, evaluating the benefit of adjuvant imatinib after complete resection of primary GIST. Correlative studies revealed that the major mechanism of acquired resistance to imatinib is the development of a second mutation in kit. Other hypotheses that are under study include those determining whether the type of mutation and intestinal site of origin predict outcome after adjuvant therapy. We recently found in a retrospective study of patients with stable metastatic GIST or resistance of a single tumor that surgery to remove residual disease appears to be useful. This observation has led to an intergroup proposal to determine whether addition of surgery to molecular therapy in stable patients might delay development of a second kit mutation, and thereby prolong time to progression. In addition to this highly focused effort, the Soft Tissue Sarcoma Disease Management Team participates extensively in the National Cancer Institute-sponsored multicenter clinical trials program, and has served as the Principal Investigator/coordinating group for seven additional NCI studies involving antiangiogenesis, immune modulatory, and chemotherapy approaches during the past period of support; these trials have assessed a variety of new agents alone or in combination with standard therapy. Clin Cancer Res. 2005;11:4182-4190. [PubMed Abstract]; Ann Surg. 2006;244:176-184. [PubMed Abstract]
- Our researchers reported that hypophosphatemia, with associated changes in bone and mineral metabolism, develops in a proportion of patients taking imatinib for either GIST or chronic myelogenous leukemia. The drug may inhibit bone remodeling, even in patients with normal serum phosphate levels. New Engl J Med. 2006;354:2006-2013. [PubMed Abstract]
- Several of our investigators are studying cell cycle-active agents. They have defined sequence-dependent interactions between flavopiridol (FLAVO) and several chemotherapy drugs and gamma-irradiation. They observed that in p53wt tumor cells, irinotecan (IRI) induces p21 and antiapoptotic proteins that result in G2 arrest without cell death; the addition of FLAVO to IRI-treated cells prevents this induction, resulting in death. Clinical trials with sequential IRI and FLAVO showed that most clinical benefit is associated with p53wt and no increase in p21 protein levels. In addition, molecular or pharmacological suppression of Drg-1 by FLAVO enhances IRI-induced apoptosis, and suppression of Drg-1 expression correlates with response to therapy. Recently, we showed that FLAVO inhibits CDK9, resulting in inhibition of RNA polymerase 2. We have demonstrated, in relatively imatinib-resistant GIST cells, that FLAVO induces apoptosis by inhibiting CDK9, suppressing transcription of c-kit. As a result, patients with imatinib-resistant GIST are now being entered onto our FLAVO clinical trials. Clin Cancer Res. 2005;11:3296-3302. [PubMed Abstract]; Cancer Res 2006;66:5858-5866. [PubMed Abstract]
- Our extensive studies of UCN-01 revealed complex and multitargeted drug effects; abandonment of its clinical development, however, caused our investigators to shift their focus to HSP90, a chaperone for chk1. The finding that 17-AAG results in its increased degradation has motivated a phase I clinical trial of 17-AAG plus IRI, with correlative study of the chk1 pathway at the maximum tolerated dose (MTD). Additional translational research programs include the testing of safingol (an inhibitor of sphingosine kinase and PKC), which induces autophagy and promotes cisplatin-induced apoptosis. Based on these data and the novel mechanism of action, a phase I clinical trial of safingol and cisplatin is now underway, with assessment of tumor apoptosis and autophagy at the MTD.
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