Targeted molecular therapy is a landmark advance in the treatment of solid cancers. Gastrointestinal stromal tumor (GIST), the most common human sarcoma, has been a model for molecular therapy because it is driven primarily by either a Kit or Pdgfr? mutation, and the small molecule inhibitor imatinib mesylate is effective against both associated oncoproteins. Previously, we have shown that part of the anti-tumor efficacy of imatinib depends on altering the intratumoral immune response to promote T cell immunity. Our goal is to optimize the use of immune therapy with molecular therapy to achieve better oncologic outcomes. Current therapy of advanced GIST relies entirely on tyrosine kinase inhibitors, since conventional chemotherapy is ineffective. While imatinib is efficacious, its effects are usually short-lived as acquired resistance develops, usually due to an additional mutation in Kit. Furthermore, some patients with GIST have primary resistance to imatinib, as their tumor never responds to treatment. Therefore, novel treatments are needed. We have discovered that the transcription factors estrogen receptor alpha and beta-catenin are critical to tumor cell survival in mouse and human GIST. In this proposal, we will investigate estrogen receptor alpha and beta-catenin inhibition in imatinib-sensitive and imatinib-resistant GIST and combine it with immunotherapy to increase anti-tumor efficacy. We will utilize three genetically engineered mouse models of GIST, two of which contain imatinib-resistant Kit mutations. We will perform correlative immunologic studies on freshly procured human GIST surgical specimens. We expect that the results will advance our understanding of the biology of GIST and lead to novel clinical trials combining immune and molecular therapy. While we are focused on GIST, our findings will have relevance to other cancers treated with targeted therapy.
In this proposal, we will investigate two proteins that we have discovered to be important in a gastrointestinal cancer. We will determine the effectiveness of targeting these proteins along with immunotherapy in mouse models. Our results may identify a more effective approach to treat patients with cancer.
|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|
|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|
Showing the most recent 10 out of 59 publications