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Cancers Jul 2020Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and...
UNLABELLED
Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models.
METHODS
Vandetanib and radiation treatment were combined in HCC cell lines grown and . In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC.
RESULTS
Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion . , combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment.
CONCLUSION
In 2D and 3D studies and in a syngeneic model , the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.
PubMed: 32668592
DOI: 10.3390/cancers12071878 -
BioRxiv : the Preprint Server For... Aug 2023Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we...
Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8 T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.
PubMed: 37609341
DOI: 10.1101/2023.08.07.552383 -
Cancer Letters Jun 2023Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of...
Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.
Topics: Humans; Animals; Mice; Cell Line, Tumor; Pancreatic Neoplasms; Cell Proliferation; Apoptosis; Receptors, Interleukin-8B; Receptors, Interleukin-8A
PubMed: 37062329
DOI: 10.1016/j.canlet.2023.216185 -
Scientific Reports Sep 2023All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment...
All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8 T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice-a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4 T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4 more than CD8 T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Interleukin-13; Interleukin-5; Tumor Microenvironment; Receptors, Retinoic Acid; Lung Neoplasms; Tretinoin; Carcinogenesis
PubMed: 37689790
DOI: 10.1038/s41598-023-41690-5 -
Journal For Immunotherapy of Cancer May 2022Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation...
BACKGROUND
Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.
METHODS
An IDH1 glioma model was created in syngeneic -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1 peptide vaccination or anti-PD-1 immune checkpoint blockade.
RESULTS
The -syngeneic IDH1 cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1 glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 gliomas. AG-881 monotherapy suppressed the progression of IDH1 gliomas in a CD4 and CD8 cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4 tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1 peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 and DR1-IDH1 peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.
CONCLUSION
The development of effective IDH1-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our -syngeneic IDH1 glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
Topics: Animals; Cancer Vaccines; Glioma; Glutarates; HLA-A2 Antigen; HLA-DR1 Antigen; Humans; Immune Checkpoint Inhibitors; Isocitrate Dehydrogenase; Mice; Mice, Transgenic; Tumor Microenvironment; Up-Regulation; Vaccines, Subunit
PubMed: 35606087
DOI: 10.1136/jitc-2022-004644 -
Current Opinion in Urology Jul 2024Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major... (Review)
Review
PURPOSE OF REVIEW
Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major challenge for the development of novel therapeutics. Preclinical models that closely mimic in vivo tumours and reflect their diverse biology are indispensable for the identification of therapies with specific activity in various BC subtypes. In this review, we summarize efforts and progress made in this context during the last 24 months.
RECENT FINDINGS
In recent years, one main focus was laid on the development of patient-derived BC models. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) were demonstrated to widely recapitulate the molecular and histopathological characteristics, as well as the drug response profiles of the corresponding tumours of origin. These models, thus, represent promising tools for drug development and personalized medicine. Besides PDXs, syngenic in vivo models are of growing importance. Since these models are generated using immunocompetent hosts, they can, amongst others, be used to develop novel immunotherapeutics and to evaluate the impact of the immune system on drug response and resistance.
SUMMARY
In the past two years, various in vivo and in vitro models closely recapitulating the biology and heterogeneity of human bladder tumours were developed.
Topics: Urinary Bladder Neoplasms; Humans; Animals; Disease Models, Animal; Organoids; Precision Medicine; Xenograft Model Antitumor Assays; Antineoplastic Agents
PubMed: 38630912
DOI: 10.1097/MOU.0000000000001182 -
Aging Cell Jul 2023Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly....
GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma.
Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of interleukin 7 (IL-7) and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term antitumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1β in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting antitumor immunity.
Topics: Mice; Animals; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-7; Cancer Vaccines; Glioblastoma
PubMed: 37165998
DOI: 10.1111/acel.13864 -
Cancer Treatment and Research... 2021Glioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker...
BACKGROUND
Glioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker candidate as well as a prognostic factor in glioblastoma patients, and we here further investigate its potential role.
MATERIALS AND METHODS
Publicly available datasets were used to compare gene expression between brain samples from glioblastoma patients and non-tumor tissue. The structure of CRP was compared between humans and rats. Glioblastoma cells from humans and rats were stained with anti-CRP. Fischer 344 rats were inoculated with syngeneic glioblastoma cells pre-coated with anti-CRP, and survival was monitored. CRP concentration in rats carrying glioblastoma was followed.
RESULTS
CRP was upregulated on one locus on gene level in glioblastoma tissue as compared to non-tumor brain tissue, but not in glioma stem cells as compared to neural stem cells. The structure of the CRP protein was a characteristic pentamer in both humans and rats. Both human and rat glioblastoma cells were clearly positive for anti-CRP staining. Pre-coating of glioblastoma cells with anti-CRP antibodies did not affect survival in rats with intracranial tumors. Serum levels of CRP increased during tumor progression but did not reach significantly different levels.
CONCLUSIONS
Both human and rat glioblastoma cells could be stained with anti-CRP antibodies in vitro. In a syngeneic glioblastoma rat model we could see an increase in serum CRP during tumor progression, but coating glioblastoma cells with anti-CRP antibodies did not provide any survival change for the animals.
Topics: Animals; Biomarkers, Tumor; Brain; Brain Neoplasms; C-Reactive Protein; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Female; Glioblastoma; Humans; Prognosis; Rats; Survival Analysis
PubMed: 33385735
DOI: 10.1016/j.ctarc.2020.100293 -
Neuro-oncology Advances 2021Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery,... (Review)
Review
Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery, chemotherapy, and ionizing radiation. Mouse models have advanced our understanding of GBM biology and the development of novel therapeutic strategies for GBM patients. However, model selection is crucial when testing developmental therapeutics, and each mouse model of GBM has unique advantages and disadvantages that can influence the validity and translatability of experimental results. To shed light on this process, we discuss the strengths and limitations of 3 types of mouse GBM models in this review: syngeneic models, genetically engineered mouse models, and xenograft models, including traditional xenograft cell lines and patient-derived xenograft models.
PubMed: 34466804
DOI: 10.1093/noajnl/vdab100 -
Cells Nov 2022As one of the leading causes of death from disease, cancer continues to pose a serious threat to human health globally. Despite the development of novel therapeutic... (Review)
Review
As one of the leading causes of death from disease, cancer continues to pose a serious threat to human health globally. Despite the development of novel therapeutic regimens and drugs, the long-term survival of cancer patients is still very low, especially for those whose diagnosis is not caught early enough. Meanwhile, our understanding of tumorigenesis is still limited. Suitable research models are essential tools for exploring cancer mechanisms and treatments. Herein we review and compare several widely used in vitro and in vivo murine cancer models, including syngeneic tumor models, genetically engineered mouse models (GEMM), cell line-derived xenografts (CDX), patient-derived xenografts (PDX), conditionally reprogrammed (CR) cells, organoids, and MiniPDX. We will summarize the methodology and feasibility of various models in terms of their advantages and limitations in the application prospects for drug discovery and development and precision medicine.
Topics: Humans; Mice; Animals; Disease Models, Animal; Neoplasms; Organoids; Precision Medicine; Heterografts
PubMed: 36497126
DOI: 10.3390/cells11233868