Scientific publications

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Scientific Publication

Nov 1, 2023 | Magazine: Cancer Discovery

Sriram Venneti #  1 , Abed Rahman Kawakibi #  1 , Sunjong Ji #  1 , Sebastian M Waszak #  2   3   4 , Stefan R Sweha #  1   5 , Mateus Mota #  1 , Matthew Pun #  1 , Akash Deogharkar  1 , Chan Chung  1   6 , Rohinton S Tarapore  7 , Samuel Ramage  7 , Andrew Chi  8 , Patrick Y Wen  9 , Isabel Arrillaga-Romany  10 , Tracy T Batchelor  11 , Nicholas A Butowski  2 , Ashley Sumrall  12 , Nicole Shonka  13 , Rebecca A Harrison  14 , John de Groot  2 , Minesh Mehta  15 , Matthew D Hall  15 , Doured Daghistani  15 , Timothy F Cloughesy  16 , Benjamin M Ellingson  16 , Kevin Beccaria  17 , Pascale Varlet  18 , Michelle M Kim  1 , Yoshie Umemura  1 , Hugh Garton  1 , Andrea Franson  1 , Jonathan Schwartz  13 , Rajan Jain  8 , Maureen Kachman  1 , Heidi Baum  1 , Charles F Burant  1 , Sophie L Mottl  3 , Rodrigo T Cartaxo  1 , Vishal John  1 , Dana Messinger  1 , Tingting Qin  1 , Erik Peterson  1 , Peter Sajjakulnukit  1 , Karthik Ravi  1 , Alyssa Waugh  1 , Dustin Walling  1 , Yujie Ding  1 , Ziyun Xia  1 , Anna Schwendeman  1 , Debra Hawes  19 , Fusheng Yang  19 , Alexander R Judkins  19 , Daniel Wahl  1 , Costas A Lyssiotis  1 , Daniel de la Nava  20   21   22 , Marta M Alonso  20   21   22 , Augustine Eze  23 , Jasper Spitzer  24   25 , Susanne V Schmidt  24   25 , Ryan J Duchatel  26   27   28 , Matthew D Dun  26   27   28 , Jason E Cain  29   30 , Li Jiang  31   32 , Sylwia A Stopka  33   34 , Gerard Baquer  33 , Michael S Regan  33 , Mariella G Filbin  31   32 , Nathalie Y R Agar  33   34   35 , Lili Zhao  1 , Chandan Kumar-Sinha  1 , Rajen Mody  1 , Arul Chinnaiyan  1 , Ryo Kurokawa  1   36 , Drew Pratt  37 , Viveka N Yadav  38 , Jacques Grill  39 , Cassie Kline  40   41 , Sabine Mueller  2   42 , Adam Resnick  40   41 , Javad Nazarian  43   44   45 , Joshua E Allen  7 , Yazmin Odia  15 , Sharon L Gardner  8 , Carl Koschmann  1


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.

CITATION  Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131

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