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Building Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model for efficacy evaluation of combinatory immunotherapie

      Background: Pancreas ductal adenocarcinoma (PDAC) has dreadful 5-year survival of 6% and remains to be one of the most difficult to treat cancer with very few standard of care options. Fueled by the clinical success of immune checkpoint inhibitors in other solid tumors, several clinical trials have been conducted in PDAC patients. Unfortunately, those attempts have achieved limited clinical benefits as single agent treatment. Now investigators are eager to test combinatory therapies of chemotherapies, small molecule immune modulators, and immune checkpoint antibodies. Highly relevant preclinical models are very much needed for proof of principle efficacy evaluation. KPC model, first described by Tuveson and colleagues as LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre, and later established a variety of derivatives by several labs with Trp53 heterozygous or homozygous knock-outs, recapitulates human PDAC tumors in many aspects including morphological small ductal tumors with enriched stromal contents; key features of immune microenvironment of PDAC representing robust inflammatory reactions, like high levels of B cells and macrophages and exclusion of effector T cells; and most importantly, non-responsive to a series of chemotherapies and immune checkpoint inhibitors, including PD1 and CTLA4 antibodies. These features make KPC model an ideal model to test combinatory therapies for PDAC. However, parental KPC model is difficult to be used for pharmacological studies due to the spontaneous nature of tumor onset and progression. The compound mutant mice are also costly to breed.
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