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 #
5R01CA102613-07
Application #
8327108
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
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$457,250
Indirect Cost
$207,250
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Seifert, Adrian M; Zeng, Shan; Zhang, Jennifer Q et al. (2016) PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. Clin Cancer Res :
Cohen, Noah A; Kim, Teresa S; DeMatteo, Ronald P (2016) Principles of Kinase Inhibitor Therapy for Solid Tumors. Ann Surg :
Cohen, Noah A; Zeng, Shan; Seifert, Adrian M et al. (2015) Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors. Cancer Res 75:2061-70
Hechtman, Jaclyn Frances; DeMatteo, Ronald; Nafa, Khedoudja et al. (2015) Additional Primary Malignancies in Patients with Gastrointestinal Stromal Tumor (GIST): A Clinicopathologic Study of 260 Patients with Molecular Analysis and Review of the Literature. Ann Surg Oncol 22:2633-9
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Cavnar, Michael J; DeMatteo, Ronald P (2014) Sarcoma response to targeted therapy dynamically polarizes tumor-associated macrophages. Oncoimmunology 3:e28463
Patwardhan, Parag P; Surriga, Oliver; Beckman, Michael J et al. (2014) Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res 20:3146-58

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