Targeted molecular agents are a landmark achievement in cancer treatment. In particular, the tyrosine kinase inhibitor imatinib mesylate targets mutant KIT protein in gastrointestinal stromal tumor (GIST), an intestinal sarcoma. While imatinib is remarkably effective, it almost never induces a complete response and tumor progression occurs at a median of approximately 20 months. During our 5 years of funding, we defined the relationship of conventional pathologic variables and the type of KIT mutation to outcome following the resection of primary GIST in humans and identified the mechanism of acquired resistance to imatinib. Our focus has evolved and now our goal is to combine immunotherapy with imatinib to improve outcomes in GIST. We hypothesize that tumor antigen release resulting from the rapid tumor destruction induced by imatinib can be exploited by using concomitant immunotherapy. In a transgenic mouse that develops GIST spontaneously, we have found that the anti-tumor effects of imatinib are partially immune-mediated. We have discovered that imatinib decreases tumor production of indoleamine 2,3-dioxygenase (IDO), a key immunosuppressive protein. We have also found that imatinib has enhanced anti-tumor efficacy when combined with antibody-mediated blockade of CTLA-4, an immunomodulatory protein expressed by activated T cells and constitutively by regulatory T cells.
In Aim 1, we will demonstrate that the anti-tumor effects of imatinib in GIST depend on inhibition of IDO.
In Aim 2, we will determine how glucocorticoid-induced tumor necrosis factor receptor ligand modulates the anti-tumor effects of imatinib.
In Aim 3, we will define how CTLA-4 blockade enhances the anti-tumor effects of imatinib in GIST. Our findings will advance our understanding of GIST and may lead to a novel clinical trial using combined molecular and immune therapy.

Public Health Relevance

In this proposal, we will investigate the role of the immune response in the effects of targeted molecular therapy against cancer. We will combine molecular therapy with immunotherapy in a mouse model of gastrointestinal cancer. Our investigations may identify a more effective approach to treating patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102613-09
Application #
8703616
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Forry, Suzanne L
Project Start
2003-07-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
9
Fiscal Year
2014
Total Cost
$443,533
Indirect Cost
$201,033
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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DeMatteo, Ronald P; Ballman, Karla V; Antonescu, Cristina R et al. (2013) Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial. Ann Surg 258:422-9
Perez, Daniel R; Baser, Raymond E; Cavnar, Michael J et al. (2013) Blood neutrophil-to-lymphocyte ratio is prognostic in gastrointestinal stromal tumor. Ann Surg Oncol 20:593-9

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