Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target
Abstract
:Simple Summary
Abstract
1. Introduction
2. Autophagy
2.1. Autophagy Types and Selectivity
2.2. Autophagy Process and Machinery
2.2.1. Autophagy Initiation
2.2.2. Autophagosome Formation
2.2.3. Autophagosome Maturation
2.2.4. Autolysosome Formation and Cargo Degradation
2.3. Upstream Autophagy Regulation
2.3.1. PI3K/AKT/mTORC1 Pathway
2.3.2. MAPK Pathway
2.3.3. AMPK
2.3.4. Beclin-1 & Bcl-2
3. Pancreatic Cancer
3.1. Current Treatment Options
3.2. Genetic Landscape of PDAC
3.2.1. KRAS
3.2.2. TP53
3.2.3. SMAD4
3.2.4. CDKN2A
3.2.5. PTEN and BRCA1/2
4. Pancreatic Tumor Microenvironment and Autophagy
4.1. Tumor Microenvironment
4.2. Pancreatic Tumor Microenvironmental Stress
4.2.1. Altered Energy Metabolism
4.2.2. Reactive Oxygen Species (ROS)
4.2.3. Acidosis
4.2.4. Hypoxia and Angiogenesis
4.2.5. Extracellular Matrix and Mechanical Stress
4.3. Supporting Cells of the Tumor Microenvironment
4.3.1. Cancer Associated Fibroblasts and Pancreatic Stellate Cells
4.3.2. Schwann Cells
4.3.3. Endothelial Progenitor Cells
4.3.4. Immune Cell Infiltration
5. Autophagy in Pancreatic Cancer Progression
5.1. Autophagic Regulation in PDAC
5.2. Autophagy Promotes Pancreatic Tumor Progression
5.3. The Role of Autophagy in Pancreatic Cancer Metastasis
5.3.1. Autophagy as a Metastasis Promoter in Pancreatic Cancer
5.3.2. Autophagy as a Metastasis Suppressor in Pancreatic Cancer
6. Inhibiting Autophagic Machinery
6.1. Targeting Late-Stage Autophagy
6.2. Targeting Autophagy Initiation
6.2.1. ULK1 Complex Inhibitors
MRT68921
SBI-0206965
6.2.2. PI3K Class III Complex Inhibitors
Spautin-1
SAR405
6.2.3. New Autophagy Initiation Inhibitors
6.3. Natural Products Targeting Autophagy
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Type of PC | Study Design | Drug and Dose | Status | Serial No. |
---|---|---|---|---|
Metastatic PDAC | Phase 2, Non-randomized, Open label | 400 mg HCQ OR 600 mg HCQ, BID for 4 weeks | Completed | NCT01273805 |
Inoperable locally advanced and metastatic PC | Phase 1, Open label, | mFOLFIRINOX (backbone) + 250 mg chlorphenesin carbamate + 200 mg HCQ, BID for 48 weeks | Recruiting | NCT05083780 |
Resectable PC | Phase 2, Open label | Photon/proton radiation during week 2 for 5 days + 825 mg/m2 capecitabine BID for 10 days + 400 mg HCQ BID from day 1 until surgery | Active not recruiting | NCT01494155 |
Metastatic PDAC, stage IV PC | Phase 1 pilot, Open label, | Binimetinib + HCQ, BID for 2 weeks | Recruiting | NCT04132505 |
Advanced PDAC, metastatic PDAC, stage IV PC | Phase 2, Open label | Paricalcitol three times weekly + HCQ BID + gemcitabine weekly + nab-paclitaxel 30 min weekly | Recruiting | NCT04524702 |
Metastatic PDAC, Stage II, Stage IIA, Stage IIB, Stage III, Stage IV PC, Unresectable PDAC | Phase 1, Open label | Trametinib QD + HCQ QD or BID for 4 weeks | Recruiting | NCT03825289 |
Advanced PDAC Metastatic PDAC | Phase 1/2, Randomized, Open label | Gemcitabine 1000 mg/m2 weekly + nab-paclitaxel 125 mg/m2 weekly OR gemcitabine 1000 mg/m2 weekly + nab-paclitaxel 125 mg/m2 weekly + HCQ 600 mg/m2 BID, for 15 days | Completed | NCT01506973 |
Pancreatic cancer | Phase 2, Randomized, Open label | Gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2, weekly for 45 days OR gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m, weekly for 45 days + HCQ 600 mg/m2 QD or BID until surgery | Completed | NCT01978184 |
Pancreatic cancer | Phase 1/2, Open label | Gemcitabine 10 mg/m2/min (dependent on dose) on day 1 and 15 + HCQ 200, 400, 600, 800, 1000, or 1200 mg BID for 31 days | Completed | NCT01128296 |
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Gillson, J.; Abd El-Aziz, Y.S.; Leck, L.Y.W.; Jansson, P.J.; Pavlakis, N.; Samra, J.S.; Mittal, A.; Sahni, S. Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target. Cancers 2022, 14, 3528. https://doi.org/10.3390/cancers14143528
Gillson J, Abd El-Aziz YS, Leck LYW, Jansson PJ, Pavlakis N, Samra JS, Mittal A, Sahni S. Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target. Cancers. 2022; 14(14):3528. https://doi.org/10.3390/cancers14143528
Chicago/Turabian StyleGillson, Josef, Yomna S. Abd El-Aziz, Lionel Y. W. Leck, Patric J. Jansson, Nick Pavlakis, Jaswinder S. Samra, Anubhav Mittal, and Sumit Sahni. 2022. "Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target" Cancers 14, no. 14: 3528. https://doi.org/10.3390/cancers14143528