Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening

被引：145

作者：

Lin, Grant L. ^{[1
]}

Wilson, Kelli M. ^{[2
]}

Ceribelli, Michele ^{[2
]}

Stanton, Benjamin Z. ^{[3
]}

Woo, Pamelyn J. ^{[1
]}

Kreimer, Sara ^{[1
]}

Qin, Elizabeth Y. ^{[1
]}

Zhang, Xiaohu ^{[2
]}

Lennon, James ^{[1
]}

Nagaraja, Surya ^{[1
]}

Morris, Patrick J. ^{[2
]}

Quezada, Michael ^{[1
]}

Gillespie, Shawn M. ^{[1
]}

Duveau, Damien Y. ^{[2
]}

Michalowski, Aleksandra M. ^{[4
]}

Shinn, Paul ^{[2
]}

Guha, Rajarshi ^{[2
]}

Ferrer, Marc ^{[2
]}

Klumpp-Thomas, Carleen ^{[2
]}

Michael, Sam ^{[2
]}

McKnight, Crystal ^{[2
]}

Minhas, Paras ^{[1
]}

Itkin, Zina ^{[2
]}

Raabe, Eric H. ^{[5
]}

Chen, Lu ^{[2
]}

Ghanem, Reem ^{[1
]}

Geraghty, Anna C. ^{[1
]}

Ni, Lijun ^{[1
]}

Andreasson, Katrin I. ^{[1
]}

Vitanza, Nicholas A. ^{[1
]}

Warren, Katherine E. ^{[1
,6
,13
]}

Thomas, Craig J. ^{[2
,7
]}

Monje, Michelle ^{[1
,8
,9
,10
,11
,12
]}

机构：

[1] Stanford Univ, Sch Med, Dept Neurol, Stanford, CA 94305 USA

[2] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[3] Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, Abigail Wexner Res Inst,Coll Med, Columbus, OH 43205 USA

[4] NCI, Lab Canc Biol, NIH, Bethesda, MD 20892 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA

[6] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA

[7] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA

[8] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA

[9] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA

[10] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[11] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA

[12] Stanford Univ, Sch Med, Stanford Inst Stem Cell & Regenerat Med, Stanford, CA 94305 USA

[13] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 519期

关键词：

CENTRAL-NERVOUS-SYSTEM; HISTONE DEACETYLASE INHIBITION; INTRINSIC PONTINE GLIOMA; PROTEASOME INHIBITOR; MULTIPLE-MYELOMA; CELL-DEATH; MARIZOMIB; MUTATIONS; APOPTOSIS; DISTINCT;

D O I：

10.1126/scitranslmed.aaw0064

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD(+)) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

引用

页数：16

共 43 条

[1] Combinatorial drug therapy for cancer in the post-genomic era [J].

Al-Lazikani, Bissan ;

Banerji, Udai ;

Workman, Paul .

NATURE BIOTECHNOLOGY, 2012, 30 (07) :679-691

[2] Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma [J].

Amengual, Jennifer E. ;

Johannet, Paul ;

Lombardo, Maximilian ;

Zullo, Kelly ;

Hoehn, Daniela ;

Bhagat, Govind ;

Scotto, Luigi ;

Jirau-Serrano, Xavier ;

Radeski, Dejan ;

Heinen, Jennifer ;

Jiang, Hongfeng ;

Cremers, Serge ;

Zhang, Yuan ;

Jones, Simon ;

O'Connor, Owen A. .

CLINICAL CANCER RESEARCH, 2015, 21 (20) :4663-4675

[3] Marizomib for central nervous system-multiple myeloma [J].

Badros, Ashraf ;

Singh, Zeba ;

Dhakal, Binod ;

Kwok, Young ;

MacLaren, Ann ;

Richardson, Paul ;

Trikha, Mohit ;

Hari, Parameswaran .

BRITISH JOURNAL OF HAEMATOLOGY, 2017, 177 (02) :221-225

[4] The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism [J].

Buglio, Daniela ;

Mamidipudi, Vidya ;

Khaskhely, Noor M. ;

Brady, Helen ;

Heise, Carla ;

Besterman, Jeffrey ;

Martell, Robert E. ;

MacBeth, Kyle ;

Younes, Anas .

BRITISH JOURNAL OF HAEMATOLOGY, 2010, 151 (04) :387-396

[5] A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib [J].

Chauhan, D ;

Catley, L ;

Li, GL ;

Podar, K ;

Hideshima, T ;

Velankar, M ;

Mitsiades, C ;

Mitsiades, N ;

Yasui, H ;

Letai, A ;

Ovaa, H ;

Berkers, C ;

Nicholson, B ;

Chao, TH ;

Neuteboom, STC ;

Richardson, P ;

Palladino, MA ;

Anderson, KC .

CANCER CELL, 2005, 8 (05) :407-419

[6] QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].

CHOU, TC ;

TALALAY, P .

ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55

[7]

Cooney T, 2018, NEURO-ONCOLOGY, V20, P53

[8] Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study [J].

Cooney, Tabitha ;

Lane, Adam ;

Bartels, Ute ;

Bouffet, Eric ;

Goldman, Stewart ;

Leary, Sarah E. S. ;

Foreman, Nicholas K. ;

Packer, Roger J. ;

Broniscer, Alberto ;

Minturn, Jane E. ;

Shih, Chie-Schin ;

Chintagumpala, Murali ;

Hassall, Tim ;

Gottardo, Nicholas G. ;

Dholaria, Hetal ;

Hoffman, Lindsey ;

Chaney, Brooklyn ;

Baugh, Joshua ;

Doughman, Renee ;

Leach, James L. ;

Jones, Blaise V. ;

Fouladi, Maryam ;

Warren, Katherine E. ;

Monje, Michelle .

NEURO-ONCOLOGY, 2017, 19 (09) :1279-1280

[9] Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier [J].

Di, Kaijun ;

Lloyd, G. Kenneth ;

Abraham, Vivek ;

MacLaren, Ann ;

Burrows, Francis J. ;

Desjardins, Annick ;

Trikha, Mohit ;

Bota, Daniela A. .

NEURO-ONCOLOGY, 2016, 18 (06) :840-848

[10] K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas [J].

Dong-Anh Khuong-Quang ;

Buczkowicz, Pawel ;

Rakopoulos, Patricia ;

Liu, Xiao-Yang ;

Fontebasso, Adam M. ;

Bouffet, Eric ;

Bartels, Ute ;

Albrecht, Steffen ;

Schwartzentruber, Jeremy ;

Letourneau, Louis ;

Bourgey, Mathieu ;

Bourque, Guillaume ;

Montpetit, Alexandre ;

Bourret, Genevieve ;

Lepage, Pierre ;

Fleming, Adam ;

Lichter, Peter ;

Kool, Marcel ;

von Deimling, Andreas ;

Sturm, Dominik ;

Korshunov, Andrey ;

Faury, Damien ;

Jones, David T. ;

Majewski, Jacek ;

Pfister, Stefan M. ;

Jabado, Nada ;

Hawkins, Cynthia .

ACTA NEUROPATHOLOGICA, 2012, 124 (03) :439-447

← 1 2 3 4 5 →