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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102613-02
Application #
6868875
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$534,976
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fairweather, Mark; Balachandran, Vinod P; Li, George Z et al. (2018) Cytoreductive Surgery for Metastatic Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors: A 2-institutional Analysis. Ann Surg 268:296-302
Vitiello, Gerardo A; Medina, Benjamin D; Zeng, Shan et al. (2018) Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor. Clin Cancer Res 24:972-984
Zhang, Jennifer Q; Zeng, Shan; Vitiello, Gerardo A et al. (2018) Macrophages and CD8+ T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors. Cancer Immunol Res 6:434-447
Cohen, Noah A; Kim, Teresa S; DeMatteo, Ronald P (2017) Principles of Kinase Inhibitor Therapy for Solid Tumors. Ann Surg 265:311-319
Zeng, Shan; Seifert, Adrian M; Zhang, Jennifer Q et al. (2017) ETV4 collaborates with Wnt/?-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor. Oncotarget 8:114195-114209
D'Angelo, Sandra P; Shoushtari, Alexander N; Keohan, Mary Louise et al. (2017) Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab. Clin Cancer Res 23:2972-2980
Lee, Ser Yee; Goh, Brian K P; Sadot, Eran et al. (2017) Surgical Strategy and Outcomes in Duodenal Gastrointestinal Stromal Tumor. Ann Surg Oncol 24:202-210
Zeng, Shan; Seifert, Adrian M; Zhang, Jennifer Q et al. (2017) Wnt/?-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor. Mol Cancer Ther 16:1954-1966
Burgoyne, Adam M; De Siena, Martina; Alkhuziem, Maha et al. (2017) Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations. JCO Precis Oncol 2017:
Seifert, Adrian M; Zeng, Shan; Zhang, Jennifer Q et al. (2017) PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. Clin Cancer Res 23:454-465

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