Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the intestinal tract. Until recently, surgery has been the only effective therapy for patients with GIST. Despite complete resection of their tumor, most patients develop, and eventually die from, recurrent disease. The majority of GISTs possess a gain of function mutation in the KIT proto-oncogene resulting in constitutive KIT protein activation and uncontrolled cell proliferation. STI571 is a small molecule that selectively inhibits KIT and a few other tyrosine kinases. It represents a landmark achievement in cancer therapeutics. STI571 validates the field of molecular oncology as it proves that a specific inhibitor can be used to target a molecular aberration responsible for the pathogenesis of neoplasia. STI571 is effective in about two-thirds of patients with metastatic GIST. Patients with primary GIST who undergo surgical resection may benefit from adjuvant STI571 and this is the subject of an ongoing CTEP sponsored Phase III randomized, double blind, placebo controlled, intergroup trial. We propose to study the tissue specimens collected from the patients enrolled in the multicenter trial. We hypothesize that the molecular characteristics of primary GIST predict the clinical outcome after adjuvant STI571 therapy. Furthermore, we postulate that subsequent molecular changes in recurrent GIST will reveal the mechanism of STI571 resistance in GIST.
In Aim 1, we will correlate specific pathologic (tumor site and size) and cytogenetic (gains of 5p, 17q, or 20q or loss of 9p) phenotype of primary GIST to recurrence and survival.
Aim 2 focuses on the relationship of KIT mutation status of primary GIST to recurrence and survival.
In Aim 3, we will compare the pathologic and molecular features of primary GIST to recurrent GIST to begin to define the molecular mechanisms of STI571 resistance. The proposed experiments represent the first prospective clinical and pathologic study of primary GIST and will reveal the natural history of GIST (placebo arm) as well as the response to an adjuvant therapy (STI571 arm). The data will set the standard for future clinicopathologic studies in primary GIST and may provide approaches to treat patients with GIST who become resistant to STI571. The results will further define GIST biology and be applicable to other diseases treated with molecular agents.
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