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Diffuse intrinsic pontine glioma (DIPG) is a group of predominantly pediatric brain tumors with an average age of diagnosis of 6–7 years old, and a poor prognosis (median survival of ~1 year). Given the location of DIPG in the brainstem, surgical approaches are limited. Furthermore, the tumors have limited responsivity to traditional chemotherapy or radiotherapy, ergo new therapeutic options are needed. Recently, the drug ONC201 has emerged as a potential therapeutic option with outcomes sometimes surpassing progression-free and expected survival outcomes. However, the selectivity of its effect and mechanism in DIPG is still unclear. Here, we pursue a better understanding of ONC201 and its mechanism of action directly in DIPG patient-derived cell lines. First, we demonstrate that a range of DIPG cell lines are highly sensitive to ONC201 and compare this sensitivity to other patient-derived brain tumor and normal controls. Next, we directly show that the mitochondrial protease, ClpP is the primary target of ONC201 in DIPG. Given recent literature implicating the activation of ClpP by ONC201 and dysregulation of the metabolome in other tumors, we are currently examining these downstream effects in DIPG. Ultimately we hope to elucidate whether ClpP targeting can be used to better diagnose and improve therapeutic options in DIPG

Emerging evidence from clinical and preclinical studies suggests that the imipridone ONC201 is well tolerated and may have some clinical impact in discrete diffuse intrinsic pontine glioma patients (DIPG). A primary goal of our work is to determine if DIPG are uniquely sensitive to ONC201 and if so, whether ONC201 itself can be used as a tool to illuminate novel vulnerabilities in DIPG. To accomplish this, we are utilizing a combination of patient-derived cell lines as well as mouse xenografts that dovetail with a variety of molecular, epigenetic and metabolomic tools. A central finding from our work is that ONC201 primarily activates the mitochondrial protease, ClpP in DIPG patient-derived cell lines, an effect consistent with recently described ONC201 mechanism of action in other tumors. We further demonstrate that activation of ClpP by ONC201 leads to a host of downstream effects in DIPG model systems including distinctive effects on the metabolome leading to direct alterations in the unique epigenetic signature of DIPG. By directly manipulating these metabolic and epigenetic factors we provide prospective mechanistic insight into how ONC201 as well as ClpP activity impacts DIPG growth and tumorigenicity. These preclinical research findings shed light on potential therapeutic vulnerabilities in DIPG as well as ways that these strategies may be combined to enhance their potential.

The imipridone ONC201 is the first selective antagonist of DRD2 for clinical oncology. Several Phase 1, Phase 1/2 and Phase 2 studies in patients with advanced cancers have established the single agent recommended Phase 2 dose (RP2D) of 625mg ONC201 administered orally once a week in adults. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent high-grade glioma in vitro, ex vivo and in vivo. Furthermore, radiographic regressions in adult recurrent H3 K27M-mutant glioblastoma patients in response to single agent ONC201 have been reported. Based on this adult experience and complementary preclinical results demonstrating the increased susceptibility of H3 K27M-mutant gliomas to ONC201, we initiated the first Phase 1 pediatric clinical trial of ONC201 January 30, 2018. This trial will determine the safety and RP2D of ONC201 in pediatric post-radiation H3 K27M-mutant glioma patients as a single agent and in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients in combination with radiation ({"type":"clinical-trial","attrs":{"text":"NCT03416530","term_id":"NCT03416530"}}NCT03416530). Patients without known H3 K27M-mutation status by a CLIA-lab can enroll with commitment to post-term biopsy. This is a multicenter, open-label, 2 arm, dose-escalation and dose-expansion study. Ten children with H3 K27M-mutant gliomas ages 5–18 years have been treated post-radiation: 3 at dose level 1; 3 at dose level 2; 4 as part of the dose expansion cohort on dose level 2. Patients have received 2–12 doses (median= 5). The ONC201 has been tolerated very well. Grade III/IV events include: decreased neutrophil count grade III (n=1) spontaneously resolved without dose modification and elevated AST grade III (n=1) returned to grade II after holding 1 dose. Additional safety data as well as pharmacokinetics, pharmacodynamics, and progression-free survival results from this trial will be reported.

Although radiotherapy is the mainstay of treatment for children with diffuse intrinsic pontine gliomas (DIPG), fewer than 10% of patients survive past two years from diagnosis despite 30 years of clinical trials. ONC201 is an oral, selective DRD2 antagonist that induces p53-independent apoptosis and has been reported to produce a durable response in an adult with a H3 K27M mutant recurrent glioblastoma. In April 2017, a 33 month old female presented with headaches, right 6(th) nerve palsy and MRI findings consistent with a DIPG. A biopsy revealed an H3.3 K27M mutant glioblastoma. A patient-derived DIPG tumorsphere cell line was created from the biopsy sample and in vitro studies revealed a potent reduction in cell viability following 5 days of treatment with ONC201, with an IC50 of approximately 600nM. She received involved field irradiation (54Gy). Starting one month following irradiation, single agent, oral ONC201 125mg (11mg/kg) was given weekly on a compassionate use protocol. An MRI, 4 months later revealed stable disease. Clinically, her 6(th) nerve palsy and left hemiparesis have improved. She is otherwise asymptomatic. Pharmacokinetic studies are being analyzed. She has had no side effects detected. Based on our in vitro and clinical findings as well as other experience in vitro and in adults, ONC201 is currently being investigated with a phase 1 trial in pediatric patients with H3 K27M mutant gliomas.

INTRODUCTION Histone H3 K27M mutations distinguish a subgroup of midline gliomas in children and young adults with devastating prognosis for which there are no effective medical therapies. In a recent phase 2 trial in adult recurrent glioblastoma with ONC201, a small molecule selective antagonist of the dopamine receptor D2 (DRD2) and D3 (DRD3), a 22 year old female with recurrent H3 K27M mutant glioblastoma had tumor regression of 92% that has persisted >15 months. Furthermore, antiseizure medication was discontinued and no ONC201 side effects were observed. Based on this exceptional response, we tested whether H3 K27M mutant gliomas were selectively sensitive to ONC201-induced apoptosis.