A5008547275- Glioma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- ATP Synthase and ATPases Research
- Neuroblastoma Research and Treatments
- Cancer therapeutics and mechanisms
- Cell death mechanisms and regulation
- PARP inhibition in cancer therapy
- Cancer Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Acute Myeloid Leukemia Research
- Histone Deacetylase Inhibitors Research
- Receptor Mechanisms and Signaling
- Cancer Cells and Metastasis
- Cancer-related Molecular Pathways
- Lung Cancer Treatments and Mutations
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Cancer Treatment and Pharmacology
- FOXO transcription factor regulation
- Microbial Metabolism and Applications
- Protein Degradation and Inhibitors
- Pharmacological Receptor Mechanisms and Effects
- Pharmacological Effects of Natural Compounds
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
Chimerix (United States)
2021-2025
Durham University
2025
University of Pennsylvania
2009-2024
Molecular Oncology (United States)
2009-2024
University of Alabama
2024
Oncoceutics (United States)
2014-2023
Wayne State University
2023
National Institute on Drug Abuse
2021
National Institutes of Health
2021
University of Nottingham
2021
TIC10 is a small molecule that activates Foxo3a through dual inactivation of Akt and ERK, up-regulates the expression TRAIL gene, an endogenous tumor suppressor, effectively improves therapeutic properties utility as anticancer therapy.
Drug target identification is a crucial step in development, yet also among the most complex. To address this, we develop BANDIT, Bayesian machine-learning approach that integrates multiple data types to predict drug binding targets. Integrating public data, BANDIT benchmarked ~90% accuracy on 2000+ small molecules. Applied 14,000+ compounds without known targets, generated ~4,000 previously unknown molecule-target predictions. From this set validate 14 novel microtubule inhibitors,...
ONC201 triggers an apoptotic cellular stress response in both solid and blood tumors.
ONC201 triggers an apoptotic cellular stress response in both solid and blood tumors.
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 two completed multisite studies. following initial radiation prior to recurrence a median overall survival of 21.7 months, whereas those after had 9.3...
Abstract Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, patients rarely surviving 2 years from diagnosis. Methods We conducted multi-site Phase 1 trial of imipridone ONC201 for children H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D (n = 24) underwent serial lumbar puncture cell-free tumor DNA (cf-tDNA) analysis and all arms at University Michigan plasma collection. performed digital droplet polymerase chain reaction...
Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), first-in-class imipridone, in recurrent H3 DMG.
Abstract Background H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, no effective systemic therapy currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients recurrent disease. This phase 3 trial evaluates newly diagnosed glioma. Methods ACTION (NCT05580562) randomized, double-blind, placebo-controlled, parallel-group, international study of Patients who have completed standard frontline...
// Isabel Arrillaga-Romany 1 , Andrew S. Chi 3 Joshua E. Allen 4 Wolfgang Oster Patrick Y. Wen 2 and Tracy T. Batchelor Stephen Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA Dana-Farber/Brigham Women's Cancer Center, Laura Isaac Perlmutter NYU Langone Medical New York, NY, Oncoceutics, Philadelphia, PA, Correspondence to: Arrillaga-Romany, email: Keywords : ONC201, Imipridone, GPCR, glioblastoma, glioma Received April 25, 2017 Accepted 28,...
Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that founding member imipridone class compounds. A first-in-human phase I study was conducted to determine its recommended II dose (RP2D).Experimental Design: This open-label treated 10 patients during escalation with histologically confirmed advanced solid tumors. Patients received orally once every 3 weeks, defined as one cycle, at doses from 125 625 mg using an accelerated titration design. An...
Abstract Self-renewing colorectal cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance therapy. Therapeutic targeting of CSCs could improve treatment response prolong patient survival. ONC201/TIC10 is a first-in-class antitumor agent that induces TRAIL pathway–mediated cell death in without observed toxicity. We have previously described exposure leads transcriptional induction the gene via transcription factor Foxo3a, which activated by dual inactivation Akt...
ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed Phase I/II trials several advanced malignancies. Binding reporter assays shown ONC201 selective antagonist dopamine D2-like receptors, specifically, DRD2 DRD3. We hypothesized ONC201's interaction with plays role anticancer effects. Using cBioportal quantitative reverse-transcription...
Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity DRD2 antagonism. This study reports first clinical experience DRD2/3 antagonist ONC201 as a potential targeted therapy for K27M-mutant DIPG. One pediatric patient (a 10-year-old girl) DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use began single-agent...
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 (NCT03416530) ONC201 for diffuse midline glioma (DMG) or intrinsic pontine (DIPG) employed dose-escalation dose-expansion design. The primary endpoint was recommended II dose (RP2D)....
Abstract Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset cell lines and primary patient samples, particularly stem cells, while producing negligible toxicity normal hematopoietic cells. suppressed mitochondrial respiration elevated α-ketoglutarate by suppressing dehydrogenase (αKGDH)...
Abstract Background Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and salvage therapy relapsed/refractory who have been treated with intensive chemotherapy. While this an important option, many fail to achieve complete remission of those that do, majority relapse. Leukemia stem cells (LSCs) are believed be responsible AML relapse can targeted through oxidative phosphorylation reduction. We previously reported ONC213 disrupts decreases...
We previously reported the identification of ONC201/TIC10, a novel small molecule inducer human TRAIL gene that improves efficacy-limiting properties recombinant and is in clinical trials advanced cancers based on its promising safety antitumor efficacy several preclinical models.
ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood-brain barrier. efficacy has been shown in glioblastoma animal models and inversely correlated with DRD5 expression. well tolerated adult recurrent patients dosing every 3 weeks achieved an objective radiographic response patient harboring H3 K27M mutation.In window-of-opportunity arm, 6 subjects initiated prior to re-resection of intratumoral concentrations as primary endpoint. An additional 20 adults received...
Abstract Purpose: The goal of this study is to enhance the efficacy imipridones, a novel class AKT/ERK inhibitors that displayed limited therapeutic against glioblastoma (GBM). Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used determine mechanism action imipridone compounds, ONC206 ONC212. Orthotopic patient-derived xenografts utilized evaluate potency. Results: Imipridones reduce proliferation xenograft stem-like cell cultures in vitro multiple...