scholarly journals Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ke Gong ◽  
Gao Guo ◽  
Nicole A. Beckley ◽  
Xiaoyao Yang ◽  
Yue Zhang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Adaptive Response ◽  
Therapeutic Resistance ◽  
Tnf Inhibitor ◽  
Adaptive Resistance ◽  
Egfr Inhibition ◽  
Rtk Signaling ◽  
Inflammatory Signals ◽  
Optimal Approach

AbstractInhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A663-A663
Author(s):  
Keegan Cooke ◽  
Juan Estrada ◽  
Jinghui Zhan ◽  
Jonathan Werner ◽  
Fei Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
T Cell Activation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

scholarly journals TMIC-24. COLONY STIMULATING FACTOR 1 INHIBITION DECREASES TUMOR GROWTH AND MACROPHAGE INFILTRATION, AND INCREASES NEUTROPHIL INFILTRATION IN XENOGRAFT MICE MODELS OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi252-vi252
Author(s):  
Sabbir Khan ◽  
Yuji Piao ◽  
Sandeep Mittal ◽  
Kain McGee ◽  
Soon Park ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Myeloid Cell ◽  
Neutrophil Infiltration ◽  
Macrophage Infiltration ◽  
Colony Stimulating Factor ◽  
Vegf Inhibitors ◽  
Mesenchymal Transition ◽  
Vegf Inhibition ◽  
Stimulating Factor

Abstract Glioblastoma (GBM) is the most common, highly aggressive and lethal primary brain tumor in adults, and has a median overall survival ranging from 12 to 15 months. Several human cancers including glioma are infiltrated with numerous immune cell types which play a critical role in tumor growth, invasion and resistance to treatment. Previous studies, including our group, have shown that resistance to anti-VEGF therapy is associated with myeloid cell infiltration and mesenchymal transition in GBM. Notably, most glioma patients have shown increase in CD68+ cells due to overproduction of colony stimulating factor 1 (CSF-1) by tumor cells, a growth factor for macrophages. Therefore, we hypothesized that CSF-1 inhibition may reduce macrophage and/or myeloid cell infiltration in glioma, thereby increasing animal survival as monotherapy or in combination with VEGF inhibitors in xenograft GBM mouse models. We tested two CSF-1R inhibitors (AZD 7507 and JNJ-28312141) alone and in combination with VEGF inhibition to prevent macrophage infiltration in xenograft GBM mouse models. CSF-1R and VEGF inhibitors reduced macrophage infiltration (F4/80 staining), tumor volume, and mesenchymal transition (YKL-40 staining), and there was a marginal survival benefit in this model. Interestingly, despite significant reduction in tumor macrophages, we observed a significant increase in neutrophil infiltration and hypoxia (HIF1α staining), particularly in the combinatorial treated. Considering these observations, we further evaluated tumor-associated neutrophil (TAN) infiltration in GBM patient tumors by fluorescence-activated cell sorting (FACS). FACS-isolated TANs were identified as CD11b+/CD15+/CD66b+ triple positive. Our results shown that the infiltrating TAN population vary from 0.5 to 5% in GBM patient tumors. Detailed characterization of TAN population and polarization in patient tumors are ongoing. Our findings revealed that CSF-1 and VEGF inhibition reduced macrophage infiltration and tumor growth, but significantly increased TAN infiltration which will likely hamper the potential therapeutic benefit of anti-CSF1-directed inhibitors.

scholarly journals Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models

Oncotarget ◽  
2017 ◽  
Vol 8 (52) ◽  
pp. 89876-89886 ◽  
Author(s):  
Caixia Wang ◽  
Yuanqiang Zheng ◽  
Michael A. Sandoval ◽  
Solange A. Valdes ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Inhibit Tumor Growth

scholarly journals Thelet-7microRNA reduces tumor growth in mouse models of lung cancer

Cell Cycle ◽  
2008 ◽  
Vol 7 (6) ◽  
pp. 759-764 ◽  
Author(s):  
Aurora Esquela-Kerscher ◽  
Phong Trang ◽  
Jason F. Wiggins ◽  
Lubna Patrawala ◽  
Angie Cheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Mouse Models

scholarly journals Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma

2020 ◽  
Vol 22 (10) ◽  
pp. 1439-1451
Author(s):  
Wen-Bin Yang ◽  
Che-Chia Hsu ◽  
Tsung-I Hsu ◽  
Jing-Ping Liou ◽  
Kwang-Yu Chang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Target Genes ◽  
Integration Site ◽  
Recurrent Glioblastoma ◽  
Stem Cell Population ◽  
Therapeutic Resistance ◽  
Low Grade ◽  
Human Telomerase Reverse Transcriptase ◽  
Resistant Cells

Abstract Background Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemoresistance and glioblastoma recurrence. The specificity protein 1 (Sp1) transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. Methods Sp1 acetylation in temozolomide-resistant cells and stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation–related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. Results We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (hTERT), as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres. Conclusion Our study uncovers a previously unknown regulatory mechanism in which the HDAC6/Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.

scholarly journals Panaxydol, a component ofPanax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models

2015 ◽  
Vol 138 (6) ◽  
pp. 1432-1441 ◽  
Author(s):  
Hee Suk Kim ◽  
Jang Mi Lim ◽  
Joo Young Kim ◽  
Yongjin Kim ◽  
Serkin Park ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Mouse Models ◽  
Egfr Activation ◽  
Apoptosis In Cancer Cells

Abstract 5242: Bioluminescence imaging of radiation induced tumor growth inhibition in orthotopic mouse models

2010 ◽  
Author(s):  
Meridith Baugher ◽  
Matt Ziemke ◽  
Erin Trachet ◽  
William Elliott ◽  
Wilbur R. Leopold ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Mouse Models ◽  
Bioluminescence Imaging ◽  
Tumor Growth Inhibition ◽  
Radiation Induced

scholarly journals TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1484
Author(s):  
Bernard Staumont ◽  
Majeed Jamakhani ◽  
Chrisostome Costa ◽  
Fabian Vandermeers ◽  
Sathya Neelature Sriramareddy ◽  
...  
Keyword(s):  
Rna Interference ◽  
Growth Factor ◽  
Tumor Growth ◽  
Mouse Models ◽  
Differentially Expressed Genes ◽  
Malignant Pleural Mesothelioma ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Differentially Expressed ◽  
Pleural Mesothelioma

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.

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