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Hepato-pancreato-biliary

P36: Increased Efficacy of a Synergistic Combination in Sensitizing Pancreatic Neuroendocrine Tumors to Radiation in vivo

Introduction: Radiation therapy in p<span style="color: black; background: white;">ancreatic neuroendocrine tumors (pNETs) promotes disease stability and increased quality of life, but only 18% of pNETs are responsive. We previously identified synergistic effects in pNET cells when combining a radionucleotide reductase inhibitor (RNRi) with an ataxia telangiectasia and Rad3 related protein inhibitor (ATRi). We hypothesized the combination of the RNRi, triapine, with the orally bioavailable ATRi, BAY1895344, would enhance DNA damage and sensitize pNETs to ionizing radiation (IR) therapy in vivo.

Methods: Experiments were performed in accordance with protocols approved by the Institution’s Animal Care and Use Committee. Human pNET cells (3x106 BON GL trained cells) were injected subcutaneously into the left flanks of immunocompromised mice, and tumors allowed to proliferate. Mice were randomly divided into 8 groups and treated with the vehicle control, 10mg/kg triapine, 20mg/kg BAY1895344, 2Gy external beam X-ray radiation, or a combination thereof. After treatment, tumors were collected for (i) immunohistochemical (IHC) staining and (ii) western blot analysis. Live zebrafish embryos were treated similarly and evaluated for (iii) morphologic changes, (iv) apoptosis, and (v) DNA damage. Statistical analyses were performed using ANOVA with Bonferroni adjustment, significance set as p< 0.05.   

Results:

(i) Tumor samples showed increased expression of cleaved-caspase 3 and Ki-67, and (ii) immunoblot analysis revealed greater expression of cleaved PARP indicating increased apoptosis with combination therapy. (iii) Zebrafish embryos treated with combination therapy (triapine+BAY+IR) had significantly greater (p< 0.001) morphological changes (i.e., shortened body length, curved spine, pericardial edema, and head/tail/yolk malformation) indicative of treatment effect. (iv) Similarly, embryos treated with combination therapy demonstrated greater apoptosis determined by acridine orange assay (Figure) and TUNEL analysis (triapine+BAY+IR 129 ± 40, BAY+IR 94 ± 49, triapine+IR 62 ± 19, IR 53 ± 26 positive cells; p< 0.001). (v) Combination therapy had statistically more DNA damage than the controls (triapine+BAY+IR 87 ± 45, BAY+IR 29 ± 19, triapine+IR 26 ± 31, IR 13 ± 5 positive cells; p< 0.001).

Conclusions:

The combination of triapine and BAY1895344 sensitized pNETs to radiation therapy in vivo and represents a novel treatment strategy for pNETs. By capitalizing on the synergy of this combination, clinical efficacy may be achieved at lower doses of radiation potentially leading to less adverse side effects for patients.

Learning Objectives:

  • Describe the utility of combination therapy in achieving greater physiologic effect.
  • Describe some of the uses of the zebrafish model in measuring drug effect.
  • Define the limitations of IR in treating pancreatic NETs.