Targeted molecular agents are a major advance in cancer therapy. The tyrosine kinase inhibitor imatinib mesylate targets the mutant KIT protein in gastrointestinal stromal tumor (GIST). However, while imatinib is highly effective against metastatic GIST, it almost never induces a complete response. Tumor progression occurs at a median of approximately 20 months and most patients eventually die from their disease. We have found that a novel tyrosine kinase inhibitor called PLX3397 is substantially more effective than imatinib in a genetically engineered mouse model of GIST and in human xenografts. After treatment, there is just a small fraction of residual tumor cells. Given that we have previously found that the immune system contributes to the efficacy of imatinib in GIST, we propose in Aim 1 to define the immune response after PLX3397 therapy in mouse GIST. Since PLX3397 causes much greater tumor destruction than imatinib, we hypothesize that the anti-tumoral immune response is greater. To eradicate the few remaining cells after PLX3397 treatment, we will combine it with the immunomodulatory agents anti-CTLA-4 or anti-PD-1 in Aim 2. The effect on tumor size and the antigen-specific CD8 T cell response will be assessed.
In Aim 3, we will determine whether human intratumoral CD8 T cells that are freshly isolated from surgical specimens are functional against GIST. We anticipate that our findings will increase our understanding of GIST and may establish the rationale for a novel clinical trial combining molecular and immune therapy in GIST. We expect that our work will not only improve the lives of patients with these tumors, but also be relevant to other cancers in which targeted molecular therapy is used.

Public Health Relevance

Targeted molecular therapies are a landmark achievement in cancer treatment. Imatinib mesylate is one such therapy, which is remarkably effective against gastrointestinal stromal tumor (GIST), a solid cancer of the stomach and intestines. However, imatinib does not cure the disease and resistance against the drug eventually develops. We have identified a drug that is more effective than imatinib. The goal of the current research is to determine if and how immune therapy may enhance the anti- tumor effects of this new agent to achieve complete eradication of GIST. The results may provide the rationale for a new clinical trial combining molecular and immune therapy in patients with GIST, as well as an approach that can be applied to other types of cancer in which targeted molecular therapy is used.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA186534-02
Application #
8989465
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakowlew, Sonia B
Project Start
2014-07-07
Project End
2016-07-06
Budget Start
2015-07-06
Budget End
2016-07-05
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
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
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
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