Citations 2
The emerging field of viroimmunotherapy for pediatric brain tumors
García-Moure, Marc , Laspidea, Virginia , Gupta, Sumit , Khatua, Soumen , Parthasarathy, Akhila , Lang, Frederick F. , Fueyo, Juàn , Gomez‐Manzano, Candelaria , Fueyo, Juan , Gomez-Manzano, Candelaria , Gillard, Andrew Gregg , He, Jiasen , Alonso, Marta M
Neuro-Oncology | August 16, 2024 | Volume: 26 | Issue: 11 | Pages: 1981-1993
Abstract Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.
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