Abstract
It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. “The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity”. Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.
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References
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.
Conroy S, Kruyt FA, Joseph JV, Balasubramaniyan V, Bhat KP, Wagemakers M, et al. Subclassification of newly diagnosed glioblastomas through an immunohistochemical approach. PLoS ONE. 2014;9:e115687.
Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Eastman C. et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro-Oncology. 2014;16:896–913.
Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y. et al. A potent blood–brain barrier-permeable mutant IDH1 inhibitor suppresses the growth of glioblastoma with IDH1 mutation in a patient-derived orthotopic Xenograft model. Mol Cancer Ther. 2020;19:375–83. https://doi.org/10.1158/1535-7163.MCT-18-1349.
Wen PY, Cloughesy TF, Olivero AG, Morrissey KM, Wilson TR, Lu X. et al. First-in-human phase I study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma. Clin Cancer Res. 2020;26:1820–8. https://doi.org/10.1158/1078-0432.CCR-19-2808.
Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018;124:3307–18.
Amaravadi RK, Kimmelman AC, Debnath J. Targeting autophagy in cancer: recent advances and future directions. Cancer Discov. 2019;9:1167–81.
Haas NB, Appleman LJ, Stein M, Redlinger M, Wilks M, Xu X. et al. Autophagy inhibition to augment mTOR inhibition: a phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin Cancer Res. 2019;25:2080–7. https://doi.org/10.1158/1078-0432.CCR-18-2204.
Hruban Z, Spargo B, Swift H, Wissler RW, Kleinfeld RG. Focal cytoplasmic degradation. Am J Pathol. 1963;42:657–83.
Hruban Z, Swift H, Wissler RW. Analog-induced inclusions in pancreatic acinar cells. J Ultrastruct Res. 1962;7:273–85.
Klionsky DJ. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4:740–3.
Xia K, Liu T, Ouyang J, Wang R, Fan T, Zhang M. Genome-wide identification, classification, and expression analysis of autophagy-associated gene homologues in rice (Oryza sativa L.). DNA Res. 2011;18:363–77.
Sheng R, Qin ZH. History and current status of autophagy research. Adv Exp Med Biol. 2019;1206:3–37.
Feng Y, He D, Yao Z, Klionsky DJ. The machinery of macroautophagy. Cell Res. 2014;24:24–41.
Molina ML, García-Bernal D, Martinez S, Valdor R. Autophagy in the immunosuppressive perivascular microenvironment of glioblastoma. Cancers. 2020;12:102.
Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep. 2008;9:859–64.
Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F. An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol. 2010;190:1005–22.
van der Vaart A, Griffith J, Reggiori F. Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol Biol Cell. 2010;21:2270–84.
Yen WL, Shintani T, Nair U, Cao Y, Richardson BC, Li Z, et al. The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J Cell Biol. 2010;188:101–14.
Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 2001;20:5971–81.
Kim J, Huang WP, Stromhaug PE, Klionsky DJ. Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J Biol Chem. 2002;277:763–73.
Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy. 2010;6:891–900.
Han J, Goldstein LA, Hou W, Chatterjee S, Burns TF, Rabinowich H. HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC. Autophagy. 2018;14:958–71.
Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008;182:685–701.
Li WW, Li J, Bao JK. Microautophagy: lesser-known self-eating. Cell Mol Life Sci. 2012;69:1125–36.
Roberts P, Moshitch-Moshkovitz S, Kvam E, O’Toole E, Winey M, Goldfarb DS. Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell. 2003;14:129–41.
Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, et al. Autophagy mediates degradation of nuclear lamina. Nature. 2015;527:105–9.
Uttenweiler A, Schwarz H, Mayer A. Microautophagic vacuole invagination requires calmodulin in a Ca2+-independent function. J Biol Chem. 2005;280:33289–97.
Doelling JH, Walker JM, Friedman EM, Thompson AR, Vierstra RD. The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J Biol Chem. 2002;277:33105–14.
Muller O, Sattler T, Flotenmeyer M, Schwarz H, Plattner H, Mayer A. Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J Cell Biol. 2000;151:519–28.
Sattler T, Mayer A. Cell-free reconstitution of microautophagic vacuole invagination and vesicle formation. J Cell Biol. 2000;151:529–38.
Wang F, Muller S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Front Immunol. 2015;6:252.
Chiang HL, Dice JF. Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem. 1988;263:6797–805.
Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22:407–17.
Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 2014;24:92–104.
Valdor R, Mocholi E, Botbol Y, Guerrero-Ros I, Chandra D, Koga H, et al. Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. Nat Immunol. 2014;15:1046–54.
Buchser WJ, Laskow TC, Pavlik PJ, Lin HM, Lotze MT. Cell-mediated autophagy promotes cancer cell survival. Cancer Res. 2012;72:2970–9.
Wojton J, Meisen WH, Kaur B. How to train glioma cells to die: molecular challenges in cell death. J Neuro-Oncol. 2016;126:377–84.
Ulasov IV, Shah N, Kaverina NV, Lee H, Lin B, Lieber A, et al. Tamoxifen improves cytopathic effect of oncolytic adenovirus in primary glioblastoma cells mediated through autophagy. Oncotarget. 2015;6:3977–87.
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222.
He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.
Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273:3963–3966. https://doi.org/10.1074/jbc.273.7.3963.
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009;136:521–534. https://doi.org/10.1016/j.cell.2008.11.044.
Long X, Ortiz-Vega S, Lin Y, Avruch J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem. 2005;280:23433–23436. https://doi.org/10.1074/jbc.C500169200.
Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 2000;150:1507–1513. https://doi.org/10.1083/jcb.150.6.1507.
Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20:1992–2003. https://doi.org/10.1091/mbc.e08-12-1249.
Hara T, Takamura A, Kishi C, Iemura SI, Natsume T, Guan JL, et al. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol. 2008;181:497–510. https://doi.org/10.1083/jcb.200712064.
Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20:1981–1991. https://doi.org/10.1091/mbc.e08-12-1248.
Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002;10:151–162. https://doi.org/10.1016/s1097-2765(02)00568-3.
Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–1834. https://doi.org/10.1101/gad.1110003.
Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003;5:578–581. https://doi.org/10.1038/ncb999.
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590. https://doi.org/10.1016/s0092-8674(03)00929-2.
Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer. 2010;10:98.
Zhang X, Li C, Wang D, Chen Q, Li CL, Li HJ. Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma. Gene. 2016;590:285–92. https://doi.org/10.1016/j.gene.2016.05.036.
Swiderek E, Kalas W, Wysokinska E, Pawlak A, Rak J, Strzadala L. The interplay between epigenetic silencing, oncogenic KRas and HIF-1 regulatory pathways in control of BNIP3 expression in human colorectal cancer cells. Biochem Biophys Res Commun. 2013;441:707–12.
White E. The role for autophagy in cancer. J Clin Invest. 2015;125:42–6.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin-1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA. 2003;100:15077–82.
Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of Beclin-1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65.
Wang ZH, Xu L, Duan ZL, Zeng LQ, Yan NH, Peng ZL. Beclin-1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol. 2007;107:107–13.
Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I, et al. Protein and mRNA expression of autophagy gene Beclin-1 in human brain tumours. Int J Oncol. 2007;30:429–36.
Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.
Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, et al. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008;13:343–54.
Wang X, Wu WKK, Gao J, Li Z, Dong B, Lin X, et al. Autophagy inhibition enhances PD-L1 expression in gastric cancer. J Exp Clin Cancer Res. 2019;38:140.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.
Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190:881–92.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51–64.
Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20:51–6.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011;25:460–70.
Jing Z, Han W, Sui X, Xie J, Pan H. Interaction of autophagy with microRNAs and their potential therapeutic implications in human cancers. Cancer Lett. 2015;356 Part B:332–8.
Zhai H, Song B, Xu X, Zhu W, Ju J. Inhibition of autophagy and tumor growth in colon cancer by miR-502. Oncogene. 2013;32:1570–9.
Chan XH, Nama S, Gopal F, Rizk P, Ramasamy S, Sundaram G, et al. Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas. Cell Rep. 2012;2:591–602.
Stojcheva N, Schechtmann G, Sass S, Roth P, Florea AM, Stefanski A, et al. MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM. Oncotarget. 2016;7:12937–50. https://doi.org/10.18632/oncotarget.7346.
Gwak HS, Kim TH, Jo GH, Kim YJ, Kwak HJ, Kim JH, et al. Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines. PLoS ONE. 2012;7:e47449.
Palumbo S, Miracco C, Pirtoli L, Comincini S. Emerging roles of microRNA in modulating cell-death processes in malignant glioma. J Cell Physiol. 2014;229:277–86.
Mollaei H, Safaralizadeh R, Rostami Z. MicroRNA replacement therapy in cancer. J Cell Physiol. 2019;234:12369–84.
Sette P, Amankulor N, Li A, Marzulli M, Leronni D, Zhang M. et al. GBM-targeted oHSV armed with matrix metalloproteinase 9 enhances anti-tumor activity and animal survival. Mol Ther Oncol. 2019;15:214–22. https://doi.org/10.1016/j.omto.2019.10.005.
Zhang C, Nance EA, Mastorakos P, Chisholm J, Berry S, Eberhart C. et al. Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats. J Control Rel. 2017;263:112–119. https://doi.org/10.1016/j.jconrel.2017.03.007.
Kim DG, Kim KH, Seo YJ, Yang H, Marcusson EG, Son E. et al. Anti-miR delivery strategies to bypass the blood–brain barrier in glioblastoma therapy. Oncotarget. 2016;7:29400–29411. https://doi.org/10.18632/oncotarget.8837.
Khan AA, Betel D, Miller ML, Sander C, Leslie CS, Marks DS. Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs [published correction appears. Nat Biotechnol. 2009;27:549–555. https://doi.org/10.1038/nbt.1543.
Stenvang J, Petri A, Lindow M, Obad S, Kauppinen S. Inhibition of microRNA function by antimiR oligonucleotides. Silence. 2012;3:1. https://doi.org/10.1186/1758-907X-3-1.
Castanotto D, Sakurai K, Lingeman R, Li H, Shively L, Aagaard L. et al. Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC. Nucleic Acids Res. 2007;35:5154–5164. https://doi.org/10.1093/nar/gkm543.
Stupp R, Mason WP, Van den bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl J Med. 2005;352:987–96.
Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F. et al. Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis. 2017;38:592–603.
Aoki H, Kondo Y, Aldape K, Yamamoto A, Iwado E, Yokoyama T. et al. Monitoring autophagy in glioblastoma with antibody against isoform B of human microtubule-associated protein 1 light chain 3. Autophagy. 2008;4:467–75.
Furuya D, Tsuji N, Yagihashi A, Watanabe N. Beclin-1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res. 2005;307:26–40.
Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res. 2001;61:439–44.
Pirtoli L, Cevenini G, Tini P, Vannini M, Oliveri G, Marsili S, et al. The prognostic role of Beclin-1 protein expression in high-grade gliomas. Autophagy. 2009;5:930–6.
D’Atri S, Tentori L, Lacal PM, Graziani G, Pagani E, Benincasa E, et al. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol. 1998;54:334–41.
Hirose Y, Berger MS, Pieper RO. p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res. 2001;61:1957–63.
Kapadia FN, Bajan KB, Singh S, Mathew B, Nath A, Wadkar S. Changing patterns of airway accidents in intubated ICU patients. Intens Care Med. 2001;27:296–300.
Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004;11:448–57.
Gratas C, Sery Q, Rabe M, Oliver L, Vallette FM. Bak and Mcl-1 are essential for temozolomide induced cell death in human glioma. Oncotarget. 2014;5:2428–35.
Natsumeda M, Aoki H, Miyahara H, Yajima N, Uzuka T, Toyoshima Y, et al. Induction of autophagy in temozolomide treated malignant gliomas. Neuropathology. 2011;31:486–93.
Lin CJ, Lee CC, Shih YL, Lin CH, Wang SH, Chen TH, et al. Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells. PLoS ONE. 2012;7:e38706.
Knizhnik AV, Roos WP, Nikolova T, Quiros S, Tomaszowski KH, Christmann M, et al. Survival and death strategies in glioma cells: autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damage. PLoS ONE. 2013;8:e55665.
Golden EB, Cho HY, Hofman FM, Louie SG, Schonthal AH, Chen TC. Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors. Neurosurg Focus. 2015;38:E12.
Golden EB, Cho HY, Jahanian A, Hofman FM, Louie SG, Schonthal AH, et al. Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus. 2014;37:E12.
Lee SW, Kim HK, Lee NH, Yi HY, Kim HS, Hong SH, et al. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 2015;360:195–204.
Geng Y, Kohli L, Klocke BJ, Roth KA. Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent. Neuro Oncol. 2010;12:473–81.
Sun N, Malide D, Liu J, Rovira II, Combs CA, Finkel T. A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat Protoc. 2017;12:1576–87.
Um JH, Kim YY, Finkel T, Yun J. Sensitive measurement of mitophagy by flow cytometry using the pH-dependent fluorescent reporter mt-Keima. J Vis Exp. 2018:58099. https://doi.org/10.3791/58099.
Hori YS, Hosoda R, Akiyama Y, Sebori R, Wanibuchi M, Mikami T, et al. Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells. J Neurooncol. 2015;122:11–20.
Eng CH, Wang Z, Tkach D, Toral-Barza L, Ugwonali S, Liu S, et al. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc Natl Acad Sci USA. 2016;113:182–7.
Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144:337–43.
Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014;10:1359–68.
Sesen J, Dahan P, Scotland SJ, Saland E, Dang VT, Lemarie A. et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS ONE. 2015;10:e0123721
Zhang ZS, Wang J, Shen YB, Guo CC, Sai KE, Chen FR, et al. Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy. Oncol Lett. 2015;10:379–83.
Bak DH, Kang SH, Choi DR, Gil MN, Yu KS, Jeong JH, et al. Autophagy enhancement contributes to the synergistic effect of vitamin D in temozolomide-based glioblastoma chemotherapy. Exp Ther Med. 2016;11:2153–62.
Gong C, Hu C, Gu F, Xia Q, Yao C, Zhang L, et al. Co-delivery of autophagy inhibitor ATG7 siRNA and docetaxel for breast cancer treatment. J Control Rel. 2017;266:272–86.
Dyczynski M, Yu Y, Otrocka M, Parpal S, Braga T, Henley AB, et al. Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib. Cancer Lett 2018;435:32–43.
Pasquier B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy 2015;11:725–6. https://doi.org/10.1080/15548627.2015.1033601.
Martin KR, Celano SL, Solitro AR, Gunaydin H, Scott M, O’Hagan RC, et al. A potent and selective ULK1 inhibitor suppresses autophagy and sensitizes cancer cells to nutrient. Stress iScience. 2018;8:74–84. https://doi.org/10.1016/j.isci.2018.09.012
Deretic V, Kimura T, Timmins G, Moseley P, Chauhan S, Mandell M. Immunologic manifestations of autophagy. J Clin Invest. 2015;125:75–84.
Jiang YG, Peng Y, Koussougbo KS. Necroptosis: a novel therapeutic target for glioblastoma. Med Hypotheses. 2011;76:350–2.
Olive PL, Durand RE. Apoptosis: an indicator of radiosensitivity in vitro? Int J Radiat Biol. 1997;71:695–707.
Shinomiya N. New concepts in radiation-induced apoptosis: ‘premitotic apoptosis’ and ‘postmitotic apoptosis’. J Cell Mol Med. 2001;5:240–53.
Lomonaco SL, Finniss S, Xiang C, Decarvalho A, Umansky F, Kalkanis SN, et al. The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int J Cancer. 2009;125:717–22.
Ito H, Daido S, Kanzawa T, Kondo S, Kondo Y. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int J Oncol. 2005;26:1401–10.
Yuan X, Du J, Hua S, Zhang H, Gu C, Wang J, et al. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells. Exp Cell Res. 2015;330:267–76.
Jinno-Oue A, Shimizu N, Hamada N, Wada S, Tanaka A, Shinagawa M, et al. Irradiation with carbon ion beams induces apoptosis, autophagy, and cellular senescence in a human glioma-derived cell line. Int J Radiat Oncol Biol Phys. 2010;76:229–41.
Ning S, Knox SJ. G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. Radiat Res. 1999;151:659–69.
Palumbo S, Comincini S. Autophagy and ionizing radiation in tumors: the “survive or not survive” dilemma. J Cell Physiol. 2013;228:1–8.
Talarico C, Dattilo V, D’antona L, Barone A, Amodio N, Belviso S. et al. SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells. Oncotarget. 2016;7:15868–84.
Johannessen TC, Hasan-olive MM, Zhu H, Denisova O, Grudic A, Latif MA, et al. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. Int J Cancer. 2019;144:1735–45.
Rebecca VW, Amaravadi RK. Emerging strategies to effectively target autophagy in cancer. Oncogene. 2016;35:1–11.
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.
Acknowledgements
This work was supported in part by funding received from NCI R01 CA181450-on “Pancreatic Ductal Adenocarcinoma is a disease of constitutive autophagy” and a subcontract on DARPA-BAA-14-14; DARPA Big Mechanism Proposal. AIMCancer: Automated Integration of Mechanisms in Cancer.
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Zhang, X., Deibert, C.P., Kim, WJ. et al. Autophagy inhibition is the next step in the treatment of glioblastoma patients following the Stupp era. Cancer Gene Ther 28, 971–983 (2021). https://doi.org/10.1038/s41417-020-0205-8
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DOI: https://doi.org/10.1038/s41417-020-0205-8
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