Citations 2
Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
Venneti, Sriram , Kawakibi, Abed Rahman , Ji, Sunjong , Waszak, Sebastian M. , Sweha, Stefan R. , Mota, Mateus , Pun, Matthew , Deogharkar, Akash , Chung, Chan , Tarapore, Rohinton S. , Ramage, Samuel , Chi, Andrew , Wen, Patrick Y. , Arrillaga‐Romany, Isabel , Batchelor, Tracy T. , Butowski, Nicholas , Shonka, Nicole , Hall, Matthew D. , Daghistani, Doured , Beccaria, Kévin , Umemura, Yoshie , Garton, Hugh , Franson, Andrea , Schwartz, Jonathan , Kachman, Maureen , Baum, Heidi , Burant, Charles , Mottl, Sophie L. , Cartaxo, Rodrigo T. , John, Vishal , Messinger, Dana , Peterson, Erik , Ravi, Karthik , Waugh, Alyssa , Walling, Dustin , Ding, Yujie , Xia, Ziyun , Hawes, Debra , Yang, Fusheng , Judkins, Alexander R. , Wahl, Daniel , Lyssiotis, Costas A. , Nava, Daniel de la , Eze, Augustine , Spitzer, Jasper , Schmidt, Susanne V. , Cain, Jason E. , Jiang, Li , Agar, Nathalie Y.R. , Zhao, Lili , Mody, Rajen , Kurokawa, Ryo , Yadav, Viveka Nand , Grill, Jacques , Kline, Cassie , Mueller, Sabine , Nazarian, Javad , Allen, Joshua E. , Odia, Yazmín , Butowski, Nicholas A , Sumrall, Ashley , Shonka, Nicole , Harrison, Rebecca A , de Groot, John , Mehta, Minesh P , Hall, Matthew D , Daghistani, Doured , Cloughesy, Timothy F , Ellingson, Benjamin M , Beccaria, Kevin , Varlet, Pascale , Kim, Michelle M , Umemura, Yoshie , Garton, Hugh , Franson, Andrea , Schwartz, Jonathan , Jain, Rajan , Kachman, Maureen , Baum, Heidi , Burant, Charles F , Mottl, Sophie L , Cartaxo, Rodrigo T , John, Vishal , Messinger, Dana , Qin, Tingting , Peterson, Erik , Sajjakulnukit, Peter , Ravi, Karthik , Waugh, Alyssa , Walling, Dustin , Ding, Yujie , Xia, Ziyun , Schwendeman, Anna , Hawes, Debra , Yang, Fusheng , Judkins, Alexander R , Wahl, Daniel , Lyssiotis, Costas A , de la Nava, Daniel , Alonso, Marta M , Eze, Augustine , Spitzer, Jasper , Schmidt, Susanne V , Duchatel, Ryan J , Dun, Matthew D , Cain, Jason E , Jiang, Li , Stopka, Sylwia A , Baquer, Gerard , Regan, Michael S , Filbin, Mariella G , Agar, Nathalie Y R , Zhao, Lili , Kumar-Sinha, Chandan , Mody, Rajen , Chinnaiyan, Arul , Kurokawa, Ryo , Pratt, Drew , Yadav, Viveka N , Grill, Jacques , Kline, Cassie , Mueller, Sabine , Resnick, Adam , Nazarian, Javad , Allen, Joshua E , Odia, Yazmin , Gardner, Sharon L , Koschmann, Carl , Tarapore, Rohinton S , Ji, Sunjong , Wen, Patrick Yung , Arrillaga‐Romany, Isabel , Sumrall, Ashley , Groot, John de , Mehta, Minesh P. , Cloughesy, Timothy F. , Ellingson, Benjamin M. , Kim, Michelle M. , Jain, Rajan , Stopka, Sylwia A. , Baquer, Gerard , Regan, Michael S. , Koschmann, Carl
Cancer Discovery | August 16, 2023 | Volume: 13 | Issue: 11 | Pages: 2370-2393
Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293
Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials
Rahman, Ruman , Janowski, Mirosław , Killick-Cole, Clare, Singleton, William , Campbell, Emma , Walczak, Piotr , Khatua, Soumen , Faltings, Lukas , Symons, Marc , Schneider, Julia , Kwan, Kevin, Boockvar, John A. , Gill, Steven , Oliveira, Joaquím M. , Beccaria, Kévin , Carpentier, Alexandre , Canney, Michael , Veal, Gareth J. , Meijer, Lisethe , Walker, David , Oliveira, J Miguel , Veal, Gareth J , Meijer, Lisethe , Carpentier, Alexandre C. , Pearl, Monica Smith
Cancers | January 30, 2023 | Volume: 15 | Issue: 3 | Pages: 857
Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30–40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood–brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.