Topics:

Clinical Trials in Soft Tissue Sarcomas

Clinical Trials in Soft Tissue Sarcomas

Soft tissue sarcomas in adults
are rare malignancies with diverse histologies that have historically been classified together, mostly
for
convenience. In truth, however, these diseases are quite biologically distinct
in their pathogenesis and clinical behavior. The molecular mechanisms underlying
sarcoma development are for the most part still poorly understood; however,
recent studies have begun to elucidate the gene mutations responsible for
oncogenesis in some of the histologic subtypes, including the SYT-SSX fusion
gene in synovial sarcoma and c-KIT in gastrointestinal stromal tumors
(GIST).[1-3] Recent studies in GIST are worthy of discussion, as they have
provided a long-awaited proof of principle for molecular targeting of aberrant
cellular pathways in solid tumors.

Gastrointestinal Stromal Tumors

Unresectable or metastatic GIST is a fatal disease that is refractory to all
chemotherapeutic interventions. KIT is a cell-surface transmembrane receptor
that has tyrosine kinase activity and regulates cell proliferation and
apoptosis. It was recently discovered that the c-KIT gene is mutated or
dysregulated in nearly all patients with GIST; this leads to constitutive
activation of KIT signaling, resulting in uncontrolled cell proliferation.[2]

Imatinib mesylate (Gleevec, Glivec) is a selective inhibitor of several
tyrosine kinases including KIT, bcr-abl, and platelet-derived growth factor
receptor. In a recently reported phase II trial, 147 patients with recurrent or
metastatic GIST treated with imatinib had an overall response rate of 54%, with
another 28% of patients achieving stable disease.[4] Based on early results from
this study, two large phase III trials were collaboratively developed and
conducted in North America and Europe. Together, these studies accrued
approximately 1,800 patients in less than 10 months.

These are remarkable achievements, demonstrating that rationally designed
molecularly targeted agents may have significant efficacy when patients whose
cancers possess the critical target are appropriately assessed and selected for
therapeutic intervention. This also affirms the ability of the Cooperative
Groups to rapidly conduct and complete important large-scale trials in these
rare diseases.

State-of-the-Science Meeting

The scientific success and clinical results of the investigations in GIST
have generated renewed excitement in sarcoma research, culminating recently in a
National Cancer Institute (NCI)-sponsored State-of-the-Science Meeting:
"Soft Tissue Sarcoma: Building on Molecular and Clinical Progress."
This conference brought together an international group of sarcoma experts from
a wide variety of disciplines including biology, pathology, surgery, radiation
oncology, imaging, and medical oncology. Among other issues, these experts
considered and discussed opportunities and obstacles for: (1) continued
identification of aberrant molecular pathways in sarcomas; (2) translating
basic research into clinical investigation; and (3) identifying the questions
that are of highest priority for clinical investigation. Interested individuals
can review the proceeds and summary recommendations of this meeting on the
Internet at www.webtie.org/SOTS/index.htm.

Pages

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.