Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective

Author(s): Maria Grazia Perrone*, Antonio Ruggiero, Antonella Centonze, Antonio Carrieri, Savina Ferorelli and Antonio Scilimati*

Volume 28, Issue 17, 2021

Published on: 06 August, 2020

Page: [3287 - 3317] Pages: 31

DOI: 10.2174/0929867327666200806110206

Price: $65


Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents.

In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential “leads” for the development of new drugs to be used in the treatment of DIPG.

In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.

Keywords: Diffuse intrinsic pontine glioma (DIPG), ONC201, ADEPs, D9, Dopamine receptors, CHOP, TRIAL, FOXO3a, ERK/AKT system, ClpP, SAR, Clinical Trials.

Harris, W. Case of pontine glioma, with special reference to the paths of gustatory sensation., Proc. R. Soc. Med., 1926, 19(Neurol Sect), 1-5..
[ ] [PMID: 19985059]
Freeman, C.R.; Farmer, J.P. Pediatric brain stem gliomas: a review. Int. J. Radiat. Oncol. Biol. Phys., 1998, 40(2), 265-271.
[] [PMID: 9457808]
Cooney, T.; Lane, A.; Bartels, U.; Bouffet, E.; Goldman, S.; Leary, S.E.S.; Foreman, N.K.; Packer, R.J.; Broniscer, A.; Minturn, J.E.; Shih, C.S.; Chintagumpala, M.; Hassall, T.; Gottardo, N.G.; Dholaria, H.; Hoffman, L.; Chaney, B.; Baugh, J.; Doughman, R.; Leach, J.L.; Jones, B.V.; Fouladi, M.; Warren, K.E.; Monje, M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro-oncol., 2017, 19(9), 1279-1280.
[] [PMID: 28821206]
Hargrave, D.; Bartels, U.; Bouffet, E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol., 2006, 7(3), 241-248.
[] [PMID: 16510333]
Gupta, N.; Goumnerova, L.C.; Manley, P.; Chi, S.N.; Neuberg, D.; Puligandla, M.; Fangusaro, J.; Goldman, S.; Tomita, T.; Alden, T.; DiPatri, A.; Rubin, J.B.; Gauvain, K.; Limbrick, D.; Leonard, J.; Geyer, J.R.; Leary, S.; Browd, S.; Wang, Z.; Sood, S.; Bendel, A.; Nagib, M.; Gardner, S.; Karajannis, M.A.; Harter, D.; Ayyanar, K.; Gump, W.; Bowers, D.C.; Weprin, B.; MacDonald, T.J.; Aguilera, D.; Brahma, B.; Robison, N.J.; Kiehna, E.; Krieger, M.; Sandler, E.; Aldana, P.; Khatib, Z.; Ragheb, J.; Bhatia, S.; Mueller, S.; Banerjee, A.; Bredlau, A-L.; Gururangan, S.; Fuchs, H.; Cohen, K.J.; Jallo, G.; Dorris, K.; Handler, M.; Comito, M.; Dias, M.; Nazemi, K.; Baird, L.; Murray, J.; Lindeman, N.; Hornick, J.L.; Malkin, H.; Sinai, C.; Greenspan, L.; Wright, K.D.; Prados, M.; Bandopadhayay, P.; Ligon, K.L.; Kieran, M.W. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro-oncol., 2018, 20(11), 1547-1555.
[] [PMID: 29741745]
Schwartzentruber, J.; Korshunov, A.; Liu, X-Y.; Jones, D.T.W.; Pfaff, E.; Jacob, K.; Sturm, D.; Fontebasso, A.M.; Quang, D.A.; Tönjes, M.; Hovestadt, V.; Albrecht, S.; Kool, M.; Nantel, A.; Konermann, C.; Lindroth, A.; Jäger, N.; Rausch, T.; Ryzhova, M.; Korbel, J-O.; Hielscher, T.; Hauser, P.; Garami, M.; Klekner, A.; Bognar, L.; Ebinger, M.; Schuhmann, M.U.; Scheurlen, W.; Pekrun, A.; Frühwald, M.C.; Roggendorf, W.; Kramm, C.; Dürken, M.; Atkinson, J.; Lepage, P.; Montpetit, A.; Zakrzewska, M.; Zakrzewski, K.; Liberski, P.P.; Dong, Z.; Siegel, P.; Kulozik, A.E.; Zapatka, M.; Guha, A.; Malkin, D.; Felsberg, J.; Reifenberger, G.; von Deimling, A.; Ichimura, K.; Collins, V.P.; Witt, H.; Milde, T.; Witt, O.; Zhang, C.; Castelo-Branco, P.; Lichter, P.; Faury, D.; Tabori, U.; Plass, C.; Majewski, J.; Pfister, S.M.; Jabado, N. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 2012, 482(7384), 226-231.
[] [PMID: 22286061]
Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol., 2016, 131(6), 803-820.
[] [PMID: 27157931]
Robison, N.J.; Kieran, M.W. Diffuse intrinsic pontine glioma: a reassessment. J. Neurooncol., 2014, 119(1), 7-15.
[] [PMID: 24792486]
Li, J.; Zhu, S.; Kozono, D.; Ng, K.; Futalan, D.; Shen, Y.; Akers, J.C.; Steed, T.; Kushwaha, D.; Schlabach, M.; Carter, B.S.; Kwon, C-H.; Furnari, F.; Cavenee, W.; Elledge, S.; Chen, C.C. Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma. Oncotarget, 2014, 5(4), 882-893.
[] [PMID: 24658464]
Langmoen, I.A.; Lundar, T.; Storm-Mathisen, I.; Lie, S.O.; Hovind, K.H. Management of pediatric pontine gliomas. Childs Nerv. Syst., 1991, 7(1), 13-15.
[] [PMID: 2054800]
Allen, J.E.; Krigsfeld, G.; Mayes, P.A.; Patel, L.; Dicker, D.T.; Patel, A.S.; Dolloff, N.G.; Messaris, E.; Scata, K.A.; Wang, W.; Zhou, J-Y.; Wu, G.S.; El-Deiry, W.S. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci. Transl. Med., 2013, 5(171)171ra17
[] [PMID: 23390247]
Caragher, S.P.; Hall, R.R.; Ahsan, R.; Ahmed, A.U. Monoamines in glioblastoma: complex biology with therapeutic potential. Neuro-oncol., 2018, 20(8), 1014-1025.
[] [PMID: 29126252]
Madhukar, N.S.; Elemento, O.; Benes, C.H.; Garnett, M.J.; Stein, M.; Bertino, J.R.; Kaufman, H.L.; Arrillaga-Romany, I.; Batchelor, T.T.; Schalop, L.; Oster, W.; Stogniew, M.; Andreeff, M.; El-Deiry, W.S.; Allen, J.E. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research (AACR), New Orleans, LA, Philadelphia (PA)April 16-20, 2016
Allen, J.E.; Krigsfeld, G.; Patel, L.; Mayes, P.A.; Dicker, D.T.; Wu, G.S.; El-Deiry, W.S. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Mol. Cancer, 2015, 14(99), 99.
[] [PMID: 25927855]
Refaat, A.; Abd-Rabou, A.; Reda, A. TRAIL combinations: the new ‘trail’ for cancer therapy.(Review) Oncol. Lett. , 2014, 7(5), 1327-1332.
[] [PMID: 24765133]
Ukrainskaya, V.M.; Stepanov, A.V.; Glagoleva, I.S.; Knorre, V.D.; Belogurov, A.A. Death receptors: new opportunities in cancer therapy. Acta Naturae, 2017, 9(3), 55-63.
[PMID: 29104776]
Dai, X.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M-E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp. Biol. Med. (Maywood), 2015, 240(6), 760-773.
[] [PMID: 25854879]
Allen, J.E.; Kline, C.L.B.; Prabhu, V.V.; Wagner, J.; Ishizawa, J.; Madhukar, N.; Lev, A.; Baumeister, M.; Zhou, L.; Lulla, A.; Stogniew, M.; Schalop, L.; Benes, C.; Kaufman, H.L.; Pottorf, R.S.; Nallaganchu, B.R.; Olson, G.L.; Al-Mulla, F.; Duvic, M.; Wu, G.S.; Dicker, D.T.; Talekar, M.K.; Lim, B.; Elemento, O.; Oster, W.; Bertino, J.; Flaherty, K.; Wang, M.L.; Borthakur, G.; Andreeff, M.; Stein, M.; El-Deiry, W.S. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget, 2016, 7(45), 74380-74392.
[] [PMID: 27602582]
Kline, C.L.B.; Van den Heuvel, A.P.; Allen, J.E.; Prabhu, V.V.; Dicker, D.T.; El-Deiry, W.S. ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases. Sci. Signal., 2016, 9(415), ra18.
[] [PMID: 26884600]
Allen, J.E.; Crowder, R.N.; El-Deiry, W.S. First-in-class small molecule ONC201 induces DR5 and cell death in tumor but not normal cells to provide a wide therapeutic index as an anti-cancer agent. PLoS One, 2015, 10(11)e0143082
[] [PMID: 26580220]
Greer, Y.E.; Porat-Shliom, N.; Nagashima, K.; Stuelten, C.; Crooks, D.; Koparde, V.N.; Gilbert, S.F.; Islam, C.; Ubaldini, A.; Ji, Y.; Gattinoni, L.; Soheilian, F.; Wang, X.; Hafner, M.; Shetty, J.; Tran, B.; Jailwala, P.; Cam, M.; Lang, M.; Voeller, D.; Reinhold, W.C.; Rajapakse, V.; Pommier, Y.; Weigert, R.; Linehan, W.M.; Lipkowitz, S. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget, 2018, 9(26), 18454-18479.
[] [PMID: 29719618]
Ralff, M.D.; Kline, C.L.B.; Küçükkase, O.C.; Wagner, J.; Lim, B.; Dicker, D.T.; Prabhu, V.V.; Oster, W.; El-Deiry, W.S. ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms. Mol. Cancer Ther., 2017, 16(7), 1290-1298.
[] [PMID: 28424227]
Ishizawa, J.; Kojima, K.; Chachad, D.; Ruvolo, P.; Ruvolo, V.; Jacamo, R.O.; Borthakur, G.; Mu, H.; Zeng, Z.; Tabe, Y.; Allen, J.E.; Wang, Z.; Ma, W.; Lee, H.C.; Orlowski, R.; Sarbassov, D.; Lorenzi, P.L.; Huang, X.; Neelapu, S.S.; McDonnell, T.; Miranda, R.N.; Wang, M.; Kantarjian, H.; Konopleva, M.; Davis, R.E.; Andreeff, M. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci. Signal., 2016, 9(415), ra17.
[] [PMID: 26884599]
Yuan, X.; Kho, D.; Xu, J.; Gajan, A.; Wu, K.; Wu, G.S. ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells. Oncotarget, 2017, 8(13), 21626-21638.
[] [PMID: 28423492]
Cao, Z.; Liao, Q.; Su, M.; Huang, K.; Jin, J.; Cao, D. AKT and ERK dual inhibitors: The way forward? Cancer Lett., 2019, 459, 30-40.
[] [PMID: 31128213]
Liu, Y.; Ao, X.; Ding, W.; Ponnusamy, M.; Wu, W.; Hao, X.; Yu, W.; Wang, Y.; Li, P.; Wang, J. Critical role of FOXO3a in carcinogenesis. Mol. Cancer, 2018, 17(1), 104.
[] [PMID: 30045773]
Hannenhalli, S.; Kaestner, K.H. The evolution of Fox genes and their role in development and disease. Nat. Rev. Genet., 2009, 10(4), 233-240.
[] [PMID: 19274050]
Nho, R.S.; Hergert, P. FoxO3a and disease progression. World J. Biol. Chem., 2014, 5(3), 346-354.
[] [PMID: 25225602]
Klotz, L-O.; Sánchez-Ramos, C.; Prieto-Arroyo, I.; Urbánek, P.; Steinbrenner, H.; Monsalve, M. Redox regulation of FoxO transcription factors. Redox Biol., 2015, 6, 51-72.
[] [PMID: 26184557]
Wang, X.; Hu, S.; Liu, L. Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically? Oncol. Lett., 2017, 13(5), 2867-2872.
[] [PMID: 28521392]
Yang, W.; Dolloff, N.G.; El-Deiry, W.S. ERK and MDM2 prey on FOXO3a. Nat. Cell Biol., 2008, 10(2), 125-126.
[] [PMID: 18246039]
Yang, J-Y.; Hung, M-C. A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin. Cancer Res., 2009, 15(3), 752-757.
[] [PMID: 19188143]
Beretta, G.L.; Corno, C.; Zaffaroni, N.; Perego, P. Role of FoxO proteins in cellular response to antitumor agents. Cancers (Basel), 2019, 11(1), 90.
[] [PMID: 30646603]
Madhukar, N.S.; Khade, P.; Huang, L.; Gayvert, K.; Galletti, G.; Stogniew, M.; Allen, J.E.; Giannakakou, P.; Elemento, O. O. A new big-data paradigm for target identification and drug discovery. bioRxiv, 2017, 134973. [Preprint paper]..
Kline, C.L.B.; Ralff, M.D.; Lulla, A.R.; Wagner, J.M.; Abbosh, P.H.; Dicker, D.T.; Allen, J.E.; El-Deiry, W.S. Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia, 2018, 20(1), 80-91.
[] [PMID: 29216597]
Prabhu, V.V.; Madhukar, N.S.; Gilvary, C.; Kline, C.L.B.; Oster, S.; El-Deiry, W.S.; Elemento, O.; Doherty, F.; VanEngelenburg, A.; Durrant, J.; Tarapore, R.S.; Deacon, S.; Charter, N.; Jung, J.; Park, D.M.; Gilbert, M.R.; Rusert, J.; Wechsler-Reya, R.; Arrillaga-Romany, I.; Batchelor, T.T.; Wen, P.Y.; Oster, W.; Allen, J.E. Dopamine receptor D5 is a modulator of tumor response to dopamine receptor D2 antagonism. Clin. Cancer Res., 2019, 25(7), 2305-2313.
[] [PMID: 30559168]
Birtwistle, J.; Baldwin, D. Role of dopamine in schizophrenia and Parkinson’s disease. Br. J. Nurs., 1998, 7(14), 832-834, 836, 838-841.
[] [PMID: 9849144]
Cheng, H.W.; Liang, Y.H.; Kuo, Y.L.; Chuu, C.P.; Lin, C.Y.; Lee, M.H.; Wu, A.T.; Yeh, C.T.; Chen, E.I.; Whang-Peng, J.; Su, C-L.; Huang, C-Y.F. Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data. Cell Death Dis., 2015, 6(5)e1753
[] [PMID: 25950483]
Chi, A.S.; Stafford, J.M.; Sen, N.; Possemato, R.; Placantonakis, D.; Hidalgo, E.T.; Harter, D.; Wisoff, J.; Golfinos, J.; Arrillaga-Romany, I.; Batchelor, T.; Wen, P.; Wakimoto, H.; Cahill, D.; Allen, J.E.; Oster, W.; Snuderl, M. Exth-42. H3K27M mutant gliomas are selectively killed by ONC201, a small molecule inhibitor of dopamine receptor D2. Neuro-Oncology, 2017, 19(suppl_6), vi81..
Stein, M.N.; Bertino, J.R.; Kaufman, H.L.; Mayer, T.; Moss, R.; Silk, A.; Chan, N.; Malhotra, J.; Rodriguez, L.; Aisner, J.; Aiken, R.D.; Haffty, B.G.; DiPaola, R.S.; Saunders, T.; Zloza, A.; Damare, S.; Beckett, Y.; Yu, B.; Najmi, S.; Gabel, C.; Dickerson, S.; Zheng, L.; El-Deiry, W.S.; Allen, J.E.; Stogniew, M.; Oster, W.; Mehnert, J.M. First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. Clin. Cancer Res., 2017, 23(15), 4163-4169.
[] [PMID: 28331050]
Stein, M.N.; Malhotra, J.; Tarapore, R.S.; Malhotra, U.; Silk, A.W.; Chan, N.; Rodriguez, L.; Aisner, J.; Aiken, R.D.; Mayer, T.; Haffty, B.G.; Newman, J.H.; Aspromonte, S.M.; Bommareddy, P.K.; Estupinian, R.; Chesson, C.B.; Sadimin, E.T.; Li, S.; Medina, D.J.; Saunders, T.; Frankel, M.; Kareddula, A.; Damare, S.; Wesolowsky, E.; Gabel, C.; El-Deiry, W.S.; Prabhu, V.V.; Allen, J.E.; Stogniew, M.; Oster, W.; Bertino, J.R.; Libutti, S.K.; Mehnert, J.M.; Zloza, A. Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration. J. Immunother. Cancer, 2019, 7(1), 136.
[] [PMID: 31118108]
Arrillaga-Romany, I.; Chi, A.S.; Allen, J.E.; Oster, W.; Wen, P.Y.; Batchelor, T.T. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget, 2017, 8(45), 79298-79304.
[] [PMID: 29108308]
Hall, M.D.; Odia, Y.; Allen, J.E.; Tarapore, R.; Khatib, Z.; Niazi, T.N.; Daghistani, D.; Schalop, L.; Chi, A.S.; Oster, W.; Mehta, M.P. First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M-mutant pediatric diffuse intrinsic pontine glioma: a case report. J. Neurosurg. Pediatr., 2019, 23(6), 1-7.
[] [PMID: 30952114]
Chi, A.S.; Tarapore, R.S.; Hall, M.D.; Shonka, N.; Gardner, S.; Umemura, Y.; Sumrall, A.; Khatib, Z.; Mueller, S.; Kline, C.; Zaky, W.; Khatua, S.; Weathers, S-P.; Odia, Y.; Niazi, T.N.; Daghistani, D.; Cherrick, I.; Korones, D.; Karajannis, M.A.; Kong, X-T.; Minturn, J.; Waanders, A.; Arillaga-Romany, I.; Batchelor, T.; Wen, P.Y.; Merdinger, K.; Schalop, L.; Stogniew, M.; Allen, J.E.; Oster, W.; Mehta, M.P. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. J. Neurooncol., 2019, 145(1), 97-105.
[] [PMID: 31456142]
Weissenrieder, J.S.; Neighbors, J.D.; Mailman, R.B.; Hohl, R.J. Cancer and the dopamine d2 receptor: a pharmacological perspective. J. Pharmacol. Exp. Ther., 2019, 370(1), 111-126.
[] [PMID: 31000578]
Wang, S.; Che, T.; Levit, A.; Shoichet, B.K.; Wacker, D.; Roth, B.L. Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature, 2018, 555(7695), 269-273.
[] [PMID: 29466326]
Oncoceutics, ONC201, Briefing Document, Oncologic Drugs Advisory Committee Pediatric Subcommittee,. 2019.
Ishizawa, J.; Zarabi, S.F.; Davis, R.E.; Halgas, O.; Nii, T.; Jitkova, Y.; Zhao, R.; St-Germain, J.; Heese, L.E.; Egan, G.; Ruvolo, V.R.; Barghout, S.H.; Nishida, Y.; Hurren, R.; Ma, W.; Gronda, M.; Link, T.; Wong, K.; Mabanglo, M.; Kojima, K.; Borthakur, G.; MacLean, N.; Ma, M.C.J.; Leber, A.B.; Minden, M.D.; Houry, W.; Kantarjian, H.; Stogniew, M.; Raught, B.; Pai, E.F.; Schimmer, A.D.; Andreeff, M. Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. Cancer Cell, 2019, 35(5), 721-737.e9.
[] [PMID: 31056398]
Wang, S.; Dougan, D.A. The direct molecular target for Imipridone ONC201 is finally established. Cancer Cell, 2019, 35(5), 707-708.
[] [PMID: 31085171]
Wong, K.S.; Houry, W.A. Chemical modulation of human mitochondrial ClpP: potential application in cancer therapeutics. ACS Chem. Biol., 2019, 14(11), 2349-2360.
[] [PMID: 31241890]
Amor, A.J.; Schmitz, K.R.; Baker, T.A.; Sauer, R.T. Roles of the ClpX IGF loops in ClpP association, dissociation, and protein degradation. Protein Sci., 2019, 28(4), 756-765.
[] [PMID: 30767302]
Pustylnikov, S.; Costabile, F.; Beghi, S.; Facciabene, A. Targeting mitochondria in cancer: current concepts and immunotherapy approaches. Transl. Res., 2018, 202, 35-51.
[] [PMID: 30144423]
Seo, J.H.; Rivadeneira, D.B.; Caino, M.C.; Chae, Y.C.; Speicher, D.W.; Tang, H.Y.; Vaira, V.; Bosari, S.; Palleschi, A.; Rampini, P.; Kossenkov, A.V.; Languino, L.R.; Altieri, D.C. The mitochondrial unfoldase-peptidase complex ClpXP controls bioenergetics stress and metastasis. PLoS Biol., 2016, 14(7)e1002507
[] [PMID: 27389535]
Wong, K.S.; Houry, W.A. Recent advances in targeting human mitochondrial. Mitochondria in Health and in Sickness; Urbani, A; Babu, M., Ed.; Springer Nature Singapore Pte. Ltd., 2019, pp. 119-142.
Moreno-Cinos, C.; Goossens, K.; Salado, I.G.; Van Der Veken, P.; De Winter, H.; Augustyns, K.; Clp, P. ClpP protease, a promising antimicrobial target. Int. J. Mol. Sci., 2019, 20(9), 2232.
[] [PMID: 31067645]
Zeiler, E.; Korotkov, V.S.; Lorenz-Baath, K.; Böttcher, T.; Sieber, S.A. Development and characterization of improved β-lactone-based anti-virulence drugs targeting ClpP. Bioorg. Med. Chem., 2012, 20(2), 583-591.
[] [PMID: 21855356]
Brötz-Oesterhelt, H.; Beyer, D.; Kroll, H.P.; Endermann, R.; Ladel, C.; Schroeder, W.; Hinzen, B.; Raddatz, S.; Paulsen, H.; Henninger, K.; Bandow, J.E.; Sahl, H-G.; Labischinski, H. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat. Med., 2005, 11(10), 1082-1087.
[] [PMID: 16200071]
Ye, F.; Li, J.; Yang, C.G. The development of small-molecule modulators for ClpP protease activity. Mol. Biosyst., 2016, 13(1), 23-31.
[] [PMID: 27831584]
Socha, A.M.; Tan, N.Y.; LaPlante, K.L.; Sello, J.K. Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent. Bioorg. Med. Chem., 2010, 18(20), 7193-7202.
[] [PMID: 20833054]
Stahl, M.; Korotkov, V.S.; Balogh, D.; Kick, L.M.; Gersch, M.; Pahl, A.; Kielkowski, P.; Richter, K.; Schneider, S.; Sieber, S.A. Selective activation of human caseinolytic protease P (ClpP). Angew. Chem. Int. Ed. Engl., 2018, 57(44), 14602-14607.
[] [PMID: 30129683]
Stein, M.N.; Mayer, T.M.; Moss, R.A.; Silk, A.W.; Chan, N.; Haffty, B.G.; DiPaola, R.S.; Beckett, Y.; Bentlyewski, E.; Zheng, L.; Fang, B.; Allen, J.E.; Mehnert, J.M. First-inhuman dose escalation study of oral ONC201 in advanced solid tumors. J. Clin. Oncol., 2015, 33(15_suppl), TPS2623-TPS2623..
Graves, P.R.; Aponte-Collazo, L.J.; Fennell, E.M.J.; Graves, A.C.; Hale, A.E.; Dicheva, N.; Herring, L.E.; Gilbert, T.S.K.; East, M.P.; McDonald, I.M.; Lockett, M.R.; Ashamalla, H.; Moorman, N.J.; Karanewsky, D.S.; Iwanowicz, E.J.; Holmuhamedov, E.; Graves, L.M. Mitochondrial protease ClpP is a target for the anticancer compounds ONC201 and related analogues. ACS Chem. Biol., 2019, 14(5), 1020-1029.
[] [PMID: 31021596]
Wagner, J.; Kline, C.L.; Ralff, M.D.; Lev, A.; Lulla, A.; Zhou, L.; Olson, G.L.; Nallaganchu, B.R.; Benes, C.H.; Allen, J.E.; Prabhu, V.V.; Stogniew, M.; Oster, W.; El-Deiry, W.S. Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle, 2017, 16(19), 1790-1799.
[] [PMID: 28489985]
Jacob, N.T.; Lockner, J.W.; Kravchenko, V.V.; Janda, K.D. Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL. Angew. Chem. Int. Ed. Engl., 2014, 53(26), 6628-6631.
[] [PMID: 24838721]
Ma, Z.; Gao, G.; Fang, K.; Sun, H. Development of novel anticancer agents with a scaffold of tetrahydropyrido[4,3-d]pyrimidine-2,4-dione. ACS Med. Chem. Lett., 2019, 10(2), 191-195.
[] [PMID: 30783502]
Xu, R.L.Y. Imidazo-pyrimidine compounds, and preparation methods and application thereof.International Patent WO2016/184437, 2016.
Iwanowicz, E.J. Protein kinase regulators.International Patent WO2018/0319872018, , 2018.
Iwanowicz, E.J. Protein kinase regulators. International Patent WO2018/031990A1 , 2018.
Allen, J.E.; Prabhu, V.V.; Stogniew, M. Imipridones for Gliomas US.Patent US2020/0022982, 2020.
Kang, S.G.; Maurizi, M.R.; Thompson, M.; Mueser, T.; Ahvazi, B. Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP. J. Struct. Biol., 2004, 148(3), 338-352.
[] [PMID: 15522782]
Wong, K.S.; Mabanglo, M.F.; Seraphim, T.V.; Mollica, A.; Mao, Y.Q.; Rizzolo, K.; Leung, E.; Moutaoufik, M.T.; Hoell, L.; Phanse, S.; Goodreid, J.; Barbosa, L.R.S.; Ramos, C.H.I.; Babu, M.; Mennella, V.; Batey, R.A.; Schimmer, A.D.; Houry, W.A. Acyldepsipeptide analogs dysregulate human mitochondrial ClpP protease activity and cause apoptotic cell death. Cell Chem. Biol., 2018, 25(8), 1017-1030.e9.
[] [PMID: 30126533]
Greenberger, J.S.; Cassady, J.R.; Levene, M.B. Radiation therapy of thalamic, midbrain and brain stem gliomas. Radiology, 1977, 122(2), 463-468.
[] [PMID: 402018]
Halperin, E.C. Pediatric brain stem tumors: patterns of treatment failure and their implications for radiotherapy. Int. J. Radiat. Oncol. Biol. Phys., 1985, 11(7), 1293-1298.
[] [PMID: 2989230]
Packer, R.J.; Boyett, J.M.; Zimmerman, R.A.; Albright, A.L.; Kaplan, A.M.; Rorke, L.B.; Selch, M.T.; Cherlow, J.M.; Finlay, J.L.; Wara, W.M. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer, 1994, 74(6), 1827-1834.
[<1827:AID-CNCR2820740628>3.0.CO;2-Q] [PMID: 8082086]
Zaghloul, M.S.; Eldebawy, E.; Ahmed, S.; Mousa, A.G.; Amin, A.; Refaat, A.; Zaky, I.; Elkhateeb, N.; Sabry, M. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother. Oncol., 2014, 111(1), 35-40.
[] [PMID: 24560760]
Janssens, G.O.; Gandola, L.; Bolle, S.; Mandeville, H.; Ramos-Albiac, M.; van Beek, K.; Benghiat, H.; Hoeben, B.; Morales La Madrid, A.; Kortmann, R.D.; Hargrave, D.; Menten, J.; Pecori, E.; Biassoni, V.; von Bueren, A.O.; van Vuurden, D.G.; Massimino, M.; Sturm, D.; Peters, M.; Kramm, C.M. Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: a matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur. J. Cancer, 2017, 73, 38-47.
[] [PMID: 28161497]
Lassaletta, A.; Strother, D.; Laperriere, N.; Hukin, J.; Vanan, M.I.; Goddard, K.; Lafay-Cousin, L.; Johnston, D.L.; Zelcer, S.; Zapotocky, M.; Rajagopal, R.; Ramaswamy, V.; Hawkins, C.; Tabori, U.; Huang, A.; Bartels, U.; Bouffet, E. Reirradiation in patients with diffuse intrinsic pontine gliomas: the Canadian experience. Pediatr. Blood Cancer, 2018, 65(6)e26988
[] [PMID: 29369515]
Freeman, C.R.; Kepner, J.; Kun, L.E.; Sanford, R.A.; Kadota, R.; Mandell, L.; Friedman, H. A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int. J. Radiat. Oncol. Biol. Phys., 2000, 47(3), 561-564.
[] [PMID: 10837936]
Kilburn, L.B.; Kocak, M.; Baxter, P.; Poussaint, T.Y.; Paulino, A.C.; McIntyre, C.; Lemenuel-Diot, A.; Lopez-Diaz, C.; Kun, L.; Chintagumpala, M.; Su, J.M.; Broniscer, A.; Baker, J.N.; Hwang, E.I.; Fouladi, M.; Boyett, J.M.; Blaney, S.M. A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas. Pediatr. Blood Cancer, 2018, 65(2) , 10.1002/pbc.26832.
[] [PMID: 29090526]
Cohen, K.J.; Heideman, R.L.; Zhou, T.; Holmes, E.J.; Lavey, R.S.; Bouffet, E.; Pollack, I.F. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro-oncol., 2011, 13(4), 410-416.
[] [PMID: 21345842]
Chassot, A.; Canale, S.; Varlet, P.; Puget, S.; Roujeau, T.; Negretti, L.; Dhermain, F.; Rialland, X.; Raquin, M.A.; Grill, J.; Dufour, C. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J. Neurooncol., 2012, 106(2), 399-407.
[] [PMID: 21858607]
Rizzo, D.; Scalzone, M.; Ruggiero, A.; Maurizi, P.; Attinà, G.; Mastrangelo, S.; Lazzareschi, I.; Ridola, V.; Colosimo, C.; Caldarelli, M.; Balducci, M.; Riccardi, R. Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise? J. Chemother., 2015, 27(2), 106-110.
[] [PMID: 25466729]
Haas-Kogan, D.A.; Banerjee, A.; Poussaint, T.Y.; Kocak, M.; Prados, M.D.; Geyer, J.R.; Fouladi, M.; Broniscer, A.; Minturn, J.E.; Pollack, I.F.; Packer, R.J.; Boyett, J.M.; Kun, L.E. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro-oncol., 2011, 13(3), 298-306.
[] [PMID: 21339191]
Pollack, I.F.; Jakacki, R.I.; Blaney, S.M.; Hancock, M.L.; Kieran, M.W.; Phillips, P.; Kun, L.E.; Friedman, H.; Packer, R.; Banerjee, A.; Geyer, J.R.; Goldman, S.; Poussaint, T.Y.; Krasin, M.J.; Wang, Y.; Hayes, M.; Murgo, A.; Weiner, S.; Boyett, J.M. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro-oncol., 2007, 9(2), 145-160.
[] [PMID: 17293590]
Jenkin, R.D.; Boesel, C.; Ertel, I.; Evans, A.; Hittle, R.; Ortega, J.; Sposto, R.; Wara, W.; Wilson, C.; Anderson, J. Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group. J. Neurosurg., 1987, 66(2), 227-233.
[] [PMID: 3806204]
Jennings, M.T.; Sposto, R.; Boyett, J.M.; Vezina, L.G.; Holmes, E.; Berger, M.S.; Bruggers, C.S.; Bruner, J.M.; Chan, K.W.; Dusenbery, K.E.; Ettinger, L.J.; Fitz, C.R.; Lafond, D.; Mandelbaum, D.E.; Massey, V.; McGuire, W.; McNeely, L.; Moulton, T.; Pollack, I.F.; Shen, V. Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children’s Cancer Group. J. Clin. Oncol., 2002, 20(16), 3431-3437.
[] [PMID: 12177103]
Ruggiero, A.; Rizzo, D.; Attinà, G.; Lazzareschi, I.; Maurizi, P.; Ridola, V.; Mastrangelo, S.; Migliorati, R.; Bertolini, P.; Colosimo, C.; Riccardi, R. Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors. J. Neurooncol., 2013, 113(3), 513-518.
[] [PMID: 23666235]
Jansen, M.H.; van Vuurden, D.G.; Vandertop, W.P.; Kaspers, G.J. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat. Rev., 2012, 38(1), 27-35.
[] [PMID: 21764221]
Ho, S.L.; Singh, R.; Zhou, Z.; Lavi, E.; Souweidane, M.M. Toxicity evaluation of prolonged convection-enhanced delivery of small-molecule kinase inhibitors in naïve rat brainstem. Childs Nerv. Syst., 2015, 31(2), 221-226.
[] [PMID: 25269544]
Luther, N.; Cheung, N.K.; Souliopoulos, E.P.; Karampelas, I.; Bassiri, D.; Edgar, M.A.; Guo, H.F.; Pastan, I.; Gutin, P.H.; Souweidane, M.M. Interstitial infusion of glioma-targeted recombinant immunotoxin 8H9scFv-PE38. Mol. Cancer Ther., 2010, 9(4), 1039-1046.
[] [PMID: 20371725]
Souweidane, M.M.; Occhiogrosso, G.; Mark, E.B.; Edgar, M.A. Interstitial infusion of IL13-PE38QQR in the rat brain stem. J. Neurooncol., 2004, 67(3), 287-293.
[] [PMID: 15164984]
Grasso, C.S.; Tang, Y.; Truffaux, N.; Berlow, N.E.; Liu, L.; Debily, M.A.; Quist, M.J.; Davis, L.E.; Huang, E.C.; Woo, P.J.; Ponnuswami, A.; Chen, S.; Johung, T.B.; Sun, W.; Kogiso, M.; Du, Y.; Qi, L.; Huang, Y.; Hütt-Cabezas, M.; Warren, K.E.; Le Dret, L.; Meltzer, P.S.; Mao, H.; Quezado, M.; van Vuurden, D.G.; Abraham, J.; Fouladi, M.; Svalina, M.N.; Wang, N.; Hawkins, C.; Nazarian, J.; Alonso, M.M.; Raabe, E.H.; Hulleman, E.; Spellman, P.T.; Li, X.N.; Keller, C.; Pal, R.; Grill, J.; Monje, M. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med., 2015, 21(6), 555-559.
[] [PMID: 25939062]
Pollack, I.F.; Stewart, C.F.; Kocak, M.; Poussaint, T.Y.; Broniscer, A.; Banerjee, A.; Douglas, J.G.; Kun, L.E.; Boyett, J.M.; Geyer, J.R. A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium. Neuro-oncol., 2011, 13(3), 290-297.
[] [PMID: 21292687]
Van Gool, S.W.; Makalowski, J.; Bonner, E.R.; Feyen, O.; Domogalla, M.P.; Prix, L.; Schirrmacher, V.; Nazarian, J.; Stuecker, W. Addition of Multimodal Immunotherapy to Combination Treatment Strategies for Children with DIPG: A Single Institution Experience. Medicines (Basel), 2020, 7(5), 29-45.
[] [PMID: 32438648]
Ensan, D.; Smil, D.; Zepeda-Velázquez, C.A.; Panagopoulos, D.; Wong, J.F.; Williams, E.P.; Adamson, R.; Bullock, A.N.; Kiyota, T.; Aman, A.; Roberts, O.G.; Edwards, A.M.; O’Meara, J.A.; Isaac, M.B.; Al-Awar, R. Targeting ALK2: an open science approach to developing therapeutics for the treatment of diffuse intrinsic pontine glioma. J. Med. Chem., 2020, 63(9), 4978-4996.
[] [PMID: 32369358]
Bailey, C.P.; Figueroa, M.; Gangadharan, A.; Yang, Y.; Romero, M.M.; Kennis, B.A.; Yadavilli, S.; Henry, V.; Collier, T.; Monje, M.; Lee, D.A.; Wang, L.; Nazarian, J.; Gopalakrishnan, V.; Zaky, W.; Becher, O.J.; Chandra, J. Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in pediatric high grade glioma (pHGG). Neuro-oncol., 2020, 22(9), 1302-1314.
[]] [PMID: 32166329]
Ralff, M.D.; Lulla, A.R.; Wagner, J.; El-Deiry, W.S. ONC201: a new treatment option being tested clinically for recurrent glioblastoma. Transl. Cancer Res., 2017, 6(Suppl. 7), S1239-S1243.
[] [PMID: 30175049]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy