Joshua E. Allen
University of Pennsylvania
Dopamine receptorCancerInternal medicineOncologyReceptorChemistryApoptosisImmunologyAntagonistGliomaIntegrated stress responseProgrammed cell deathDopamine receptor D2Cancer researchMedicineProtein kinase BCell cultureBiologyCancer cellPharmacology
216Publications
25H-index
1,868Citations
Publications 223
Newest
#3Bing Xie (NIDA: National Institute on Drug Abuse)H-Index: 33
ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its poten...
Source
Source
#1Chi Lam Au Yeung (University of Texas MD Anderson Cancer Center)H-Index: 2
#2Wen Hu (University of Texas MD Anderson Cancer Center)H-Index: 1
Last. Samuel C. Mok (University of Texas MD Anderson Cancer Center)H-Index: 80
view all 7 authors...
Advanced ovarian cancer (stages III and IV) is the most lethal gynecologic malignancy in the United States. Survival of this cancer has not improved to a major extent over the past decade. High-grade serous ovarian cancer (HGSC), in particular, is notable for its initial sensitivity to chemotherapy using platinum and taxane combination following debulking surgery. However, the vast majority of these cancers (>75-80%) recur within 12-24 months after diagnosis, and patients die of progressively ch...
Source
#1Robyn Borsuk (Brown University)H-Index: 1
#2Lanlan Zhou (Brown University)H-Index: 15
Last. Wafik S. El-Deiry (Brown University)H-Index: 122
view all 8 authors...
ONC201, a first-in-class, small molecule, imipridone therapy, is known to induce apoptosis via upregulation of TNF-related apoptosis inducing ligand (TRAIL) and its proapoptotic death receptor (DR5), independent of p53. Current trials have been exploring ONC201 as a monotherapy or in conjunction with radiotherapy, in treatment of patients with newly diagnosed and refractory diffuse intrinsic pontine gliomas (DIPG), a disease which remains incurable at present. We sought to identify synergy betwe...
Source
#1Sara MorrowH-Index: 1
#2Rohinton TaraporeH-Index: 17
Last. Joshua E. AllenH-Index: 25
view all 10 authors...
Imipridone ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients with once weekly dosing. We evaluated the toxicology, absorption, distribution, metabolism and excretion of ONC201 in animals. Repeat-dose 28-day studies with weekly oral ONC201 in rats and dogs revealed NOAELs (75 and 60 mg/kg, respectively) that represent higher dose levels compared to the 625 mg clinical dose. Genotoxicity (AMES,...
Source
#1Yiqun Zhang (Brown University)H-Index: 1
#2Lanlan Zhou (Brown University)H-Index: 15
Last. Wafik S. El-Deiry (Brown University)H-Index: 122
view all 6 authors...
First-in-class small molecule ONC201 is an anti-cancer agent that activates the TRAIL pathway through ATF4 and the integrated stress response (ISR). ONC201 demonstrated durable tumor regressions and prolonged disease stabilization in some patients with histone H3K27M-mutated diffuse midline glioma (DMG). The H3K27M-mutation reduces H3K27 methylation. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. We hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H...
Source
#1Sara MorrowH-Index: 1
Last. Varun Vijay PrabhuH-Index: 19
view all 10 authors...
Imipridone ONC201 is a first-in-class dopamine receptor D2 (DRD2) antagonist and mitochondrial protease ClpP agonist that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a chemical derivative of ONC201 currently in Phase I trials for central nervous system tumors, is also a DRD2 and ClpP dual targeting imipridone with differentiated target engagement and nanomolar potency. We explored molecular differentiation and predictive biomarker studies fo...
Source
#1Ling He (UCLA: University of California, Los Angeles)H-Index: 26
#2Kruttika Bhat (UCLA: University of California, Los Angeles)H-Index: 10
Last. Harley I. Kornblum (Semel Institute for Neuroscience and Human Behavior)H-Index: 66
view all 11 authors...
Abstract null null Background null Glioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells (GICs), responsible for therapy resistance and tumor recurrence, suggesting that targeting GICs could improve treatment response. ONC201 is a first-in-class anti-tumor agent with cl...
1 CitationsSource
#7Javad Nazarian (Boston Children's Hospital)H-Index: 28
#8Sabine Mueller (Boston Children's Hospital)H-Index: 36
Source
Source