Recent New Insights into the Heavy-Ion Radiobiology of Pancreatic Cancer

Pancreatic cancer is a typical refractory solid tumor with the worst prognosis. High linear energy transfer (LET) irradiation has therapeutic advantages over conventional low LET irradiation. The present study will provide recent new insight into the high LET carbon-ion radiobiology of pancreatic cancer . Human pancreatic cells PANC1, PK45, BxPc3, MIA PaCa-2, and cancer stem cells (CSCs) sorted from those of cell lines were treated with carbon ion beam alone or in combination with DNA damaging drugs (gemcitabine or 5-FU) or molecular targeting reagent (miR200c mimic), and then cell viability assay, clonogenic and sphere formation ability assay, quantitative real-time PCR assay, and xenograft tumor growth control and immunohistochemistry (IHC) analyses were carried out. The relative biological effectiveness (RBE) values for the carbon ion beams relative to X-rays at the D10 levels for CSCs were 2.1-2.4. The colony and spheroid formation capability of CSCs were significantly inhibited by carbon ion beam combined with gemcitabine or with micro RNA 200c mimic. Carbon ion beam combined with gemcitabine or miR200c mimic significantly induced expressions of apoptosis-, autophagy- and angiogenesis-related genes such as BAX, Beclin1, p62, compared to carbon ion alone or X-ray combined with gemcitabine or miR200c mimic. Carbon-ion beam combined with gemcitabine or 5-FU effectively destroyed xenograft tumors compared to carbon ion beam alone with a relatively low doses. Carbon-ion beam with high doses induced expression of LC3, Beclin1, and suppressed expression of E-cadherin, HIF1a in pancreatic xenograft tumors. Taken together, carbon ion beam combined with DNA damaging drugs or with miR200c mimic has superior advantages to eleminate pancreatic CSCs, and can promote radiocurability compared to carbon ion beam alone.The International Symposium on Ion Therapy 2018 (ISIT2018