Soft Tissue Sarcoma -- Clinical Research Program

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 8,000 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:

Molecular Pathology

  • We developed a gene-expression classifier for liposarcoma and identified potential therapeutic targets. MDM2 was found to be a particularly promising target for well-differentiated and dedifferentiated liposarcoma that is characterized by amplification of MDM2. This research supports the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes that overexpress MDM2. Cancer Res. 2007 Jul 15;67(14):6626-36. [PubMed Abstract]
  • We reported for the first time the presence of EWSR1-CREB1 in angiomatoid fibrous histiocytoma. EWSR1-CREB1 appears to be the most frequent gene fusion in this tumor type. Genes Chromosomes Cancer. 2007 Dec;46(12):1051-60. [PubMed Abstract]
  • We developed novel markers for subclinical metastatic disease for the Ewing family of tumors. Clin Cancer Res. 2007 Dec 1;13(23):6978-83. [PubMed Abstract]
  • We defined the pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors (GISTs). Second-site KIT mutations are rare in imatinib-responsive GISTs compared with imatinib-resistant tumors. The gene signature of imatinib-response in GISTs showed alterations of cell-cycle control as well as up-regulation of genes involved in muscle differentiation and function compared with imatinib-naive GISTs. Clin Cancer Res. 2007 Jan 1;13(1):170-81. [PubMed Abstract]
  • We found that pediatric GISTs have a distinct transcriptional signature, suggesting a biology that is different from GISTs in adults. Also, in vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GISTs. Clin Cancer Res. 2008 May 15;14(10):3204-15. [PubMed Abstract]
  • We developed a ten-gene microarray-based predictor that distinguished alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) with approximately 95 percent accuracy both in our data by cross-validation and in an independent validation using a published dataset of 26 samples. The gene-expression signature of ARMS provides a source of potential diagnostic markers, therapeutic targets, and PAX-FKHR downstream genes, and can be used to reliably distinguish these sarcomas from ERMS. J Pathol. 2007 Jun; 212(2):143-51. [PubMed Abstract]
  • We demonstrated that DKK1, a Wnt inhibitor and mediator of human mesenchymal stem cell (hMSC) proliferation, is overexpressed in malignant fibrous histiocytoma (MFH). We showed that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, that MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. These results provide mechanistic insights regarding the cell of origin of MFH, establish a novel tumor-suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for some types of sarcomas. J Clin Invest. 2007 Nov; 117(11):3248-57. [PubMed Abstract]

Radiation Therapy

  • We demonstrated that intensity-modulated radiation therapy (IMRT) in soft tissue sarcomas of the extremities provides excellent local control in a group of patients with high-risk features. (The five-year actuarial local control rate was 94 percent.) This finding suggests that the precision with which the IMRT dose is distributed has a beneficiary effect in sparing normal tissue and improving local control. J Clin Oncol. 2008 Jul 10;26(20):3440-4. [PubMed Abstract]

Targeted Therapies

  • We demonstrated through in vitro drug screening that the second-generation kinase inhibitors nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against wild-type KIT and that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GISTs than imatinib. Clin Cancer Res. 2008 May 15;14(10):3204-15. [PubMed Abstract]
  • We identified primary BRAF V600E mutations in 7 percent of adult GIST patients who were lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for location in the small bowel and a high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset. Genes Chromosomes Cancer. 2008 Oct;47(10):853-9. [PubMed Abstract]
  • We demonstrated that malignant peripheral nerve sheath tumors (MPNSTs) were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G(1) cell-cycle arrest. The research suggests that sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST. Mol Cancer Ther. 2008 Apr; 7(4):890-6. [PubMed Abstract]
  • We demonstrated the need for tailored salvage therapy in imatinib-refractory GISTs according to individual molecular mechanisms of resistance. The Ba/F3 KIT(WK557-8del/T670I) cells were sensitive only to sorafenib inhibition, whereas nilotinib was more potent on imatinib-resistant KIT(V560del/V654A) and KIT(V559D/D820Y) mutant cells than dasatinib and sorafenib were. Clin Cancer Res. 2007 Aug 15;13(16):4874-81. [PubMed Abstract]
  • We developed a transgenic model of leiomyosarcoma by genetically inactivating PTEN in the smooth-muscle cell lineage, cross-breeding Pten (loxP/loxP) mice with Tagln-cre mice. We showed that the rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten(loxP/loxP) mice and prolonged their life spans. These results show the critical role for the AKT-mTOR pathway in smooth-muscle transformation and leiomyosarcoma genesis, and support treatment of select sarcomas with new compounds targeting this pathway. Nat Med. 2007 Jun; 13(6):748-53. [PubMed Abstract]
  • We found that MET is a potential therapeutic target in cancers that contain TFE3 fusion proteins. We showed that aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers such as alveolar soft part sarcoma become dependent on MET signaling. This has led to Memorial Sloan Kettering involvement in an industrial phase I study of a MET inhibitor. Cancer Res. 2007 Feb 1;67(3):919-29. [PubMed Abstract]
  • We demonstrated that patients operated for GISTs live longer without their disease coming back if they receive the drug imatinib as an adjuvant therapy after surgery. Lancet. 2009 Mar 28;373(9669):1097-104. [PubMed Abstract]

Drug Combinations

  • We demonstrated that gemcitabine-docetaxel yielded superior progression-free survival and, for the first time for patients with metastatic disease, superior overall survival compared with gemcitabine alone in patients with metastatic soft tissue sarcoma. The treatment did, however, have increased toxicity. J Clin Oncol. 2007 Jul 1;25(19):2755-63. [PubMed Abstract]