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- W3178797415 abstract "In this study, we develop a novel autophagy inhibitor targeting one of the most aggressive cell populations present in pancreatic tumors, the pancreatic cancer stem cell (CSC). Targeting this population which has the malignant properties of tumorigenesis/tumor recurrence, the ability to differentiate into a heterogenous tumor cell types and can self-renew is a new strategy to alleviate the current dismal 10% five-year survival rate of pancreatic cancer. Here we characterize an autophagy inhibitor which is a first-in-class nanoparticle comprised of a chloroquine-derived small molecule drug that can self-assemble into a micelle. Due to its favorable pharmacokinetic properties and the CSC reliance on autophagy, our compound is able to selectively target this cell population both in vitro and in vivo. Additionally, the compound has shown synergy with the current standard of care chemotherapeutic, gemcitabine, with an 88.9% reduction in tumor volume in the combination of the two drugs compared to gemcitabine treated alone (p<0.0001) in two separate treatment regimens using a pancreatic PDX mouse model. We further illustrate that the stem cell population is targeted by inhibiting tumorsphere formation in established pancreatic cancer cell lines MIA-PaCa2 and PANC-1 and in pancreatic PDX-derived CSCs in vitro. The drug treatment also promotes a decrease in pluripotency markers, particularly in Sox2 levels. Finally, the drug is well-tolerated with a maximum tolerated dose above 100 mg/kg in mice and is orally bioavailable.Citation Format: Mythili Ramachandran, Zhao Ma, Yuanpei Li. Novel autophagy inhibitor to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1323." @default.
- W3178797415 created "2021-07-19" @default.
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- W3178797415 date "2021-07-01" @default.
- W3178797415 modified "2023-10-17" @default.
- W3178797415 title "Abstract 1323: Novel autophagy inhibitor to treat pancreatic cancer" @default.
- W3178797415 doi "https://doi.org/10.1158/1538-7445.am2021-1323" @default.
- W3178797415 hasPublicationYear "2021" @default.
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