Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody

Cancer Biology & Therapy
Laurence BoothPaul Dent

Abstract

Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have demonstrated the safety and efficacy of combinatorial radio-chemotherapy plus surgery in this malignancy, including the combination of sorafenib and vorinostat. The lethality of [sorafenib + vorinostat] was enhanced by gemcitabine. Exposure to [sorafenib + vorinostat] reduced the expression of β-catenin, ERBB1, BCL-XL and MCL-1, and the phosphorylation of AKT T308, AKT S473, GSK3 S9/21, mTORC1 and mTORC2. The drug combination increased the expression of Beclin1 and the phosphorylation of eIF2α S51. The drug combination rapidly reduced the levels of multiple HDAC proteins that was directly associated with the previously noted changes in tumor cell biology, as well as with alterations in the expression of biomarkers predictive for a response to checkpoint inhibitor antibodies. In vivo studies using the PAN02 model in its syngeneic mouse demonstrated that an anti-PD-1 antibody had no impact on tumor growth whereas a transient exposure to [sorafenib + vorinostat] significantly suppressed growth. The combination of [sorafenib + vorinostat] with an anti-PD-1 antibody caused a s...Continue Reading

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Citations

Jan 28, 2020·Journal of Cellular Physiology·Paul DentJohn F Hancock
Aug 8, 2020·Nature Reviews. Clinical Oncology·Lorenzo GalluzziGuido Kroemer
Dec 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Floris J van DalenOlga Ilina
Nov 12, 2019·Expert Opinion on Therapeutic Targets·Laurence BoothPaul Dent
Oct 8, 2020·International Journal of Molecular Sciences·Magdalena HuberMatthias Lauth
Jul 29, 2021·Journal of Drug Targeting·Yingying LiGuangxi Zhai

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Methods Mentioned

BETA
antibody array
transfection

Clinical Trials Mentioned

NCT01075113
NCT02349867

Software Mentioned

Sigma Plot
PhotoShop
Adobe Photoshop
MAGPIX
PowerPoint
SigmaPlot

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