Related Experiment Video
Updated: Oct 9, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the
Sai Preethi Nakkina1, Sarah B Gitto2,3,4, Jordan M Beardsley1
1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.
Insights
Difluoromethylornithine (DFMO) effectively targets MYC in pancreatic cancer, reducing tumor growth and enhancing immune cell activity. This approach shows promise for overcoming immune suppression in pancreatic ductal adenocarcinoma (PDAC) treatment.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits poor survival rates (<10%) due to immune suppression and chemoresistance.
- Tumor-associated macrophages and oncogenes like KRAS and MYC contribute to immune evasion and therapeutic challenges in PDAC.
Purpose of the Study:
- To evaluate the efficacy of targeting KRAS (via c-RAF inhibition with GW5074) and MYC (via difluoromethylornithine, DFMO) in PDAC.
- To investigate the impact of these targeted therapies on PDAC growth, immune suppression, and survival.
Main Methods:
- In vitro assessment of PDAC cell viability with DFMO and GW5074.
- In vivo studies using immunocompromised and immunocompetent syngeneic mouse models of PDAC.
- Immunohistochemical analysis to evaluate tumor immune cell infiltration and oncogene expression.
Main Results:
- Both DFMO and GW5074 reduced in vitro PDAC cell viability and in vivo tumor growth in immunocompromised mice.
- In immunocompetent mice, DFMO and combination treatment decreased tumor size, but only DFMO significantly increased survival.
- DFMO diminished MYC expression and increased infiltration of macrophages, CD86+, CD4+, and CD8+ T lymphocytes, while GW5074 did not effectively modulate these factors.
Conclusions:
- Targeting MYC with DFMO shows potential for modulating PDAC immunosuppression and improving therapeutic outcomes.
- DFMO demonstrates superior efficacy compared to GW5074 in enhancing anti-tumor immunity and survival in PDAC models.
More Related Videos
07:55Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
06:16Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Related Concept Videos
02:17The Tumor Microenvironment
02:23Abnormal Proliferation