Sam Spitzer

Introduction. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and deadly neoplastic disease of the pancreas that currently boasts a 5-year survival rate less than 10%, making it one of the deadliest attainable cancers.¹ PDAC is currently the fourth-leading cause of cancer related death and is forecasted by 2030 to become the second leading cause of cancer-mortality behind lung cancer.² PDAC eludes effective therapeutic intervention due to the unique and robust nature of its tumor microenvironment, which develops after multiple successive mutations within the patient’s pancreatic mucosa.³ There is currently a limited arsenal to combat this cancer, but research into EphrinB2 inhibition and stimulator of interferon genes (STING) agonists demonstrate the potential for advancement in PDAC therapeutic options. Methods. EphrinB2 inhibition was achieved through B11, an antibody capable of negating the protein’s effects. Murine tumor models were developed utilizing patient derived PDAC xenografts. When the murine tumors reached 100 mm³, treatment was initiated comparing the effect of PBS (control), PBS with radiotherapy, B11, and B11 with radiotherapy upon tumor volume.⁴ With STING agonist, two murine PDAC cell lines were obtained and implanted in RAG1 knockout mice. These mice were then given either no treatment, Gemcitabine, DMXAA (STING agonist), or DMXAA with Gemcitabine. The effect of treatments on tumor size and growth was then examined.¹ Results. EphrinB2 inhibition combined with radiotherapy was shown to be beneficial, demonstrating a significant increase in tumor control when compared to PBS or radiotherapy alone. Radiotherapy alone increased levels of IFNγ and TNFα on CD8+ and CD4+ T cells, administration of B11 further enhanced this effect. B11 treatment decreased levels of intratumoral Treg cells, which are immunosuppressive.⁴ STING agonist combined with Gemcitabine synergistically enhanced anti-tumor immune response, though STING agonist alone showed increased survival rates when compared to Gemcitabine alone. STING agonist was able to achieve complete tumor regression in 50% of murine tumor models.¹ Conclusion. Rates of diagnosis and mortality for patients with PDAC are on the rise. There is currently a vacuum with regard to effective therapeutic options to placate PDAC trends. Surgical intervention is the only potential curative option, while Gemcitabine, the current mainstay chemotherapeutic agent, when compared to surgery, increases overall survival by a mere 3 months.⁵ Vigorous research is ongoing, and avenues such as EphrinB2 inhibition as well as STING agonist demonstrate promising results in murine models.

1. Jing, W., McAllister, D., Vonderhaar, E. P., Palen, K., Riese, M. J., Gershan, J., Johnson, B. D., & Dwinell, M. B. (2019). STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models. Journal for ImmunoTherapy of Cancer, 7(1), np. https://doi.org/10.1186/s40425-019-0573-5
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4. Lennon S, Oweida A, Milner D, et al. Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination. Clinical Cancer Research. 2019;25(11):3352-3365. doi:10.1158/1078-0432.ccr-18-2811
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