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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Forry, Suzanne L
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Sloan-Kettering Institute for Cancer Research
New York
United States
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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
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
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
Bosbach, Benedikt; Rossi, Ferdinand; Yozgat, Yasemin et al. (2017) Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 114:E8448-E8457
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

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