Table 4.
Combinatorial Treatment with Imipridones
| Imipridone | Drug | Results | Ref. |
|---|---|---|---|
| ONC201 | Everolimus (mTOR inhibitor) | • Strongly synergized to induce apoptosis in prostate cancer cells in vitro, and potently reduced tumor growth in vivo | 16 |
| • Reduced phosphorylation of mTOR downstream targets S6 and 4EBP1 | |||
| ONC201 | AZD-8055 (mTOR inhibitor) | • AZD-8066 sensitized colorectal cancer cells to ONC201 cytotoxicity | 56 |
| • Combination treatment increased caspase-8 activation and apoptosis | |||
| ONC201 | Sorafenib (multi-kinase inhibitor) | • Increased apoptosis induction in certain hepatocellular carcinoma cell lines (HepG2) | 61 |
| • Increased tumor regression in HepG2 mouse models without toxicity or weight loss | |||
| ONC201 | Gemcitabine (DNA synthesis inhibitor) | • ONC201 sensitized pancreatic cancer cells to gemcitabine-induced growth inhibition and apoptosis induction in vitro | 53 |
| • ONC201 and gemcitabine synergized in vivo to inhibit tumor growth and improve survival in pancreatic cancer mouse models | |||
| ONC201 | OTX015 (bromodomain BRD2-4 inhibitor, c-myc antagonist) | • Combination treatment increased apoptosis in glioblastoma cells | 10 |
| ONC201 | Cytarabine (anti-metabolic agent) | • Synergized to increase cytotoxicity in pediatric non-Hodgkin’s lymphoma cells | 24 |
| • Combination is in phase 1/2 clinical trial (NCT02392572) for leukemia (Table 2) | |||
| ONC201 | ABT263 (BH-3 mimetic) | • Combination decreased anti-apoptotic Bcl-2 protein MCL-1 | 30 |
| • Increased tumor regression in in vivo glioblastoma models without toxicity | |||
| ONC201 | 2-Deoxyglucose (2-DG, glucose analog and glycolysis inhibitor) | • ONC201 and 2-DG synergized to reduce cell viability and deplete ATP in glioblastoma cell lines | 38 |
| • Slightly enhanced the fraction of cells arrested at G2/M compared to single agent treatment | |||
| • Reduced tumor growth and migration | |||
| ONC212 | NCT-503 or CBR-5884 (PDGDH inhibitors) | • Dual inhibition of mitochondrial OXPHOS (via ONC212) and the SOG pathway (via PDGDH inhibition) enhanced apoptosis induction in vitro, and reduced tumor size in vivo, in glioblastoma and colon carcinoma models | 10 |
| ONC212 | ABT-199 (Bcl-2 inhibitor) | • ONC212 reduced levels of MCL-1, a resistance factor for Bcl-2 inhibition in AML, thereby sensitizing cells to Bcl-2 inhibition by ABT-199 | 12 |
| • ONC212 and ABT-199 increased apoptosis in in vitro and in vivo AML models, and prolonged survival in in vivo MCL models | |||
| ONC201/ONC212 | AG1024 (IGF1-R inhibitor) | • Synergized to reduce cell viability in 4 out of 4 pancreatic cancer in vitro | 9 |
| • Reduced tumor size in pancreatic cancer mouse model more effectively than either agent alone |
Abbreviations: mTOR, Mammalian Target of Rapamycin; AML, acute myeloid leukemia.
aThe table lists promising drug combinations with imipridones in preclinical cancer models, which may hold potential for future clinical translation.