How ONC201 Became an Unlikely Foe for Relapsed Leukemias
Acute leukemias—particularly acute myeloid leukemia (AML)—represent one of oncology's most formidable challenges. With ~20,000 new U.S. cases annually and a median diagnosis age of 68, AML disproportionately strikes older adults 3 . Despite decades of research, standard chemotherapy ("7+3" regimen: 7 days cytarabine + 3 days daunorubicin) cures fewer than 30% of patients. For those who relapse—nearly 50% of AML patients—survival plummets to under 6 months. The urgency for novel therapies is palpable 3 .
Enter ONC201: an oral, first-in-class imipridone initially designed to target dopamine receptor D2 (DRD2) in brain cancers. Unexpectedly, early trials revealed tantalizing activity against leukemias, launching Phase I/II studies (NCT02392572) for relapsed/refractory AML, ALL, and high-risk MDS 4 .
ONC201's primary target, DRD2, belongs to the G protein-coupled receptor (GPCR) family—proteins regulating cell signaling. While highly expressed in neurological tissues, DRD2 is overexpressed in 70% of AML blasts, where it hijacks growth pathways. By blocking DRD2, ONC201:
| Mechanism | Biological Consequence | Therapeutic Impact |
|---|---|---|
| DRD2 antagonism | Prolactin elevation (blood biomarker) | Confirms target engagement 1 |
| CLPP protease activation | Mitochondrial fragmentation | Depletes energy in cancer cells |
| eIF2α phosphorylation | Global translation shutdown | Halts tumor protein production 2 |
| H3K27me3 upregulation | Epigenetic reprogramming | Reverses H3K27M mutation effects |
In 2023, researchers uncovered a bombshell: ONC201 directly binds mitochondrial protease CLPP. This hyperactivates CLPP, triggering:
This explained ONC201's efficacy in H3K27M-mutant cancers (e.g., diffuse midline gliomas), with parallel implications for leukemias sharing metabolic vulnerabilities.
The Phase I/II study enrolled 120 relapsed/refractory patients (AML/ALL/MDS) at MD Anderson. The design tackled two unknowns: optimal dosing and synergy with chemotherapy 4 .
| Arm | Regimen | Cycle Length | Phase | Key Objective |
|---|---|---|---|---|
| A | ONC201 every 3 weeks | 21 days | I/II | Establish MTD as monotherapy |
| B | ONC201 weekly | 21 days | I | Test frequent dosing |
| E | ONC201 daily + cytarabine | 28 days | I/II | Evaluate combination |
Dose escalation used an accelerated titration design:
Pharmacokinetics (PK) were tracked via LC-MS/MS plasma assays at 30 min→168 hrs post-dose. Pharmacodynamics (PD) relied on biomarkers:
Safety First: No grade >1 drug-related adverse events occurred. The RP2D was set at 625 mg every 3 weeks—the highest tested dose 2 4 .
| Population | Regimen | Median OS | Notable Responses |
|---|---|---|---|
| Recurrent glioblastoma 1 | ONC201 q3wk | 41.6 weeks | 85% tumor regression in H3K27M+ patient |
| H3K27M-DMG post-radiation | ONC201 q3wk | 21.7 months | 40.9% PR rate in ONC201-018 trial |
| Relapsed AML (NCT02392572) 4 | ONC201 + cytarabine | Pending | Prolonged SD in endometrial/prostate cases |
Though objective responses were scarce in solid tumor Phase I, prolonged stable disease (>9 cycles) occurred in prostate/endometrial cancers. For leukemias, full results remain pending, but H3K27M-mutant tumors showed striking sensitivity:
| Reagent/Method | Role in ONC201 Development | Insights Generated |
|---|---|---|
| LC-MS/MS plasma assay | Quantify ONC201 concentrations | Cmax = 1.5–7.5 μg/mL; Half-life = 11.3 hrs 2 |
| Prolactin ELISA | Surrogate marker of DRD2 blockade | Confirmed target engagement at ≥2 hrs post-dose 1 |
| Caspase-cleaved K18 | Serum apoptosis indicator | Correlated with ONC201-induced cell death 2 |
| RNA sequencing | Tumor molecular profiling | High TCA cycle gene expression → better response |
| H3K27me3 IHC | Epigenetic modification detection | ONC201 reverses H3K27me3 loss in DMG |
| Didecylbenzene | 33377-22-9 | C26H46 |
| Helospectin II | 93585-83-2 | C180H288N46O57 |
| Formolglycerin | 68442-91-1 | C4H10O4 |
| 7-Bromogramine | 852391-39-0 | C11H13BrN2 |
| Aureobasidin I | 127785-69-7 | C60H92N8O11 |
ONC201's journey illuminates a new therapeutic paradigm: targeting neurotransmitter receptors and mitochondrial proteases in cancer. Ongoing strategies include:
Identifying TCA cycle gene signatures predictive of response
ONC201 + low-dose cytarabine (Arm E) to exploit synergistic stress induction 4
Weekly vs. q3wk schedules to sustain ISR activation 4
For leukemia patients out of options, ONC201 represents more than a drug—it's proof that even relapsed cancers have metabolic Achilles' heels. As one researcher noted, "We're teaching an old receptor new tricks."
"The large tail of survival curves—30% alive at 24 months—suggests we're on the cusp of a breakthrough."