DF/HCC Program Affiliation

Leader, Sarcoma Program
Member, Translational Pharmacology and Early Therapeutic Trials Program
Member, Gastrointestinal Malignancies Program

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Sarcomas are a microcosm of solid tumor oncology: different sarcomas are increasingly being defined by molecular signatures and biological characteristics rather than by simple histopathology. Our group is translating this research on the basic biology of sarcomas into new therapeutics directed at novel targets. The foremost example of our team's work has been the development of tyrosine kinase inhibitors as effective therapies for patients with gastrointestinal stromal tumor (GIST). By targeting the specific molecular signals of GIST, we have validated the concept that a human solid tumor can be treated by signal transduction inhibitors. This work led to the development and FDA approval of imatinib mesylate (Gleevec) as an effective therapy for patients with metastatic or unresectable GIST, and serves as the basis for our ongoing research in other novel agents, such as the kinase inhibitor SU11248. We also are developing additional molecular-targeted strategies to help us better understand and treat GIST. Another example of molecular targeting of sarcomas in drug development is our pioneering interest in differentiation therapy for patients with liposarcomas (cancers of fat). This research targets a nuclear receptor known as PPARgamma, which plays a role in the normal development of fat cells, and induces differentiation in liposarcomas to decresase proliferation. Larger studies based on our pilot data are now being designed to test the clinical value of this treatment, which we are refining with newer agents and methods. Our group also is developing other agents against sarcomas, such as the natural product known as ET-743, derived from a marine organism. This drug, which binds to the DNA minor groove, has shown important clinical activity against several subtypes of sarcomas both in the laboratory and in extensive clinical trials. We are optimizing the dosage for this agent and moving forward in collaboration with other cancer centers to test the worth of this new drug. Our multidisciplinary research team, including dedicated representatives from surgical oncology, radiation oncology, pathology, and other clinical arenas, works closely with laboratory investigators so that we can offer new treatments with promise and scientific merit to patients with sarcomas of soft tissue and bone.

Publications

• Demetri GD. Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development. Hematol Oncol Clin North Am 2002 Oct; 16(5):1115-24
  PMID: 12512386
• Ryan DP, Puchalski T, Supko JG, Harmon D, Maki R, Garcia-Carbonero R, Kuhlman C, Winkelman J, Merriam P, Quigley T, Jimeno J, Manola J, Demetri GD. A phase II and pharmacokinetic study of ecteinascidin 743 in patients with gastrointestinal stromal tumors. Oncologist 2002; 7(6):531-8
  PMID: 12490740
• Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol 2002 Nov; 3(11):655-64
  PMID: 12424067
• Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joen. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002 Aug 15; 347(7):472-80
  PMID: 12181401
• Demetri GD. ET-743: the US experience in sarcomas of soft tissues. Anticancer Drugs 2002 May; 13 Suppl 1:S7-9
  PMID: 12173492
• Brooks BJ, Bani JC, Fletcher CD, Demeteri GD. Challenges in oncology. Case 4. Response of metastatic gastrointestinal stromal tumor including CNS involvement to imatinib mesylate (STI-571). J Clin Oncol 2002 Feb 1; 20(3):870-2
  PMID: 11821475
• Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Demetri GD, Fletcher CD, Fletcher JA. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001 Nov 15; 61(22):8118-21
  PMID: 11719439
• Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001 Aug 16; 20(36):5054-8
  PMID: 11526490
• Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001 Apr 5; 344(14):1052-6
  PMID: 11287975