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
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, Karen, Chapman, Paul F., Nilsen, Steven P. , Eckman, Chris, Harigaya, Yasuo, Younkin, Steven G. , Yang, Fusheng , Cole, Greg M., Ashe, Karen H. , Cole, G. M. , Cole, Gregory M.
Science | July 27, 2002 | Volume: 274 | Issue: 5284 | Pages: 99-103
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys 670 → Asn, Met 671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Aβ(1-40) and a 14-fold increase in Aβ(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Aβ plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Aβ. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.