Kurokawa, Ryo
Mayo Clinic
University of Michigan, Ann Arbor, Michigan.
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
Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
Tarapore, Rohinton S. , Allen, Jeffrey, McGovern, Susan L. , Zaky, Wafik , Odia, Yazmín , Daghistani, Doured , Hall, Matthew D. , Khatib, Ziad, Cantor, Evan , Kurokawa, Ryo , MacDonald, Tobey J. , Aguilera, Dolly , Vitanza, Nicholas A. , Kline, Cassie , Lu, Guangrong , Allen, Joshua E. , Khatua, Soumen , Tarapore, Rohinton S , Koschmann, Carl , Khatua, Soumen , Hall, Matthew D , Kurokawa, Ryo , Odia, Yazmin , Gardner, Sharon L , Allen, Jeffrey C. , Allen, Jeffrey, Diaz, Zuanel , Koschmann, Carl , Mueller, Sabine C.
Neuro-Oncology Advances | September 13, 2022 | Volume: 4 | Issue: 1 | Pages: No page available
Abstract Background ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. Methods This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. Results The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T1/2, 8.4 h; Tmax, 2.1 h; Cmax, 2.3 µg/mL; AUC0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis. Conclusions The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.