- |||||||||| ONC206 / Chimerix
ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma (Section 9) - Mar 5, 2024 - Abstract #AACR2024AACR_8620;
Mice from both Group 3 PDXs also responded to ONC206, with 25% of ONC206 treated animals exhibiting long-term tumor-free survival. Our results highlight ONC206 as a novel attractive therapeutic option for patients with relapsed medulloblastoma and importantly pave the way for a clinical trial testing the efficacy of ONC206 in the treatment of these patients.
- |||||||||| ONC206 / Chimerix
Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5483;
P1
There are two ongoing clinical trials with ONC206: single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms (NCT04541082) and ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors (NCT04732065). Future studies evaluating the role of immune function, mitochondrial metabolism, dopamine receptors, the ISR and TRAIL pathway in the synergistic effect would support further development of the triple combination regimen of ONC206, TMZ and radiation therapy for GBM clinical trial.
- |||||||||| ONC206 / Chimerix, dordaviprone (ONC201) / Chimerix
Impact of hypoxia on the integrated stress response activated by imipridones ONC201 and ONC206 in pediatric diffuse midline glioma cells (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_5278;
P=N/A, P1
Imipridones mediate apoptosis through the upregulation of the TRAIL death receptor DR5 and the activation of the integrated stress response (ISR), so western blots were used to show changes in the ISR protein expression in ONC201 treated DMG cells at multiple different degrees of hypoxia. To understand how hypoxia inducible factors (HIFs) play a role in resistance and susceptibility to ONC201 or ONC206, HIF-1a, HIF-2a, and HIF-3a were knocked down showing altered ISR protein expression after treating with the imipridones under hypoxic and normoxic conditions.
- |||||||||| Journal, Epigenetic controller: Novel combination of imipridones and histone deacetylase inhibitors demonstrate cytotoxic effect through integrated stress response in pediatric solid tumors. (Pubmed Central) - Jan 8, 2024
ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response...Additionally, pediatric solid tumor cells were treated with single-agent therapy with histone deacetylase inhibitors (HDACi) vorinostat, entinostat, and panobinostat, showing cell killing with all 3 HDACi drugs, with panobinostat showing the greatest potency...Our results introduce a novel class of small molecules to treat pediatric solid tumors in a precision medicine framework. Use of impridones in pediatric oncology is novel and shows promising pre-clinical efficacy in pediatric solid tumors, including in combination with HDAC inhibitors.
- |||||||||| ONC206 / Chimerix
Single agent and combinatorial efficacy with imipridone ONC206 via inhibition of mitochondrial function in preclinical models of chemorefractory triple negative breast cancer (Hall 2-3) - Nov 4, 2023 - Abstract #SABCS2023SABCS_728;
ONC201, a parent molecule of ONC206, has shown efficacy in TNBC as a single agent or when combined with a MEK inhibitor in vitro (PMID: 34680527)...ONC206 treatment of BCM-0002 resulted in prolonged tumor stasis and a slight enhancement of docetaxel and carboplatin efficacy...Our study underscores the potentially crucial role of mitochondria in driving chemotherapy resistance in TNBC and provides novel insights into mitochondria-targeted therapeutic approaches. We report a novel targeting option for TNBC and anticipate that these findings will stimulate further research into innovative combination therapies for TNBC patients, and may lead us to a viable inhibitor.
- |||||||||| Imipridones induce lipid peroxidation and oxidative stress in gastrointestinal malignancies (Section 10; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_7527;
Lipid peroxidation was reversed by the ferroptosis inhibitor liproxstatin-1, suggesting that in addition to inducing apoptosis, imipridones may be involved in ferroptosis induction. Future directions include mechanistic work, investigation of the effect of imipridone-induced lipid peroxidation on immune cell cytotoxicity, and understanding the relative importance of lipid peroxidation in the clinical efficacy of imipridones.
- |||||||||| ONC206 / Chimerix, dordaviprone (ONC201) / Chimerix
Role of ClpP in the anti-cancer effects of imipridone ONC201 and ONC206 (Section 14; Poster Board #25) - Mar 14, 2023 - Abstract #AACR2023AACR_7257;
Whole genome sequencing revealed ClpP mutations in both ONC201Res and ONC206Res cells. Our results confirm the role of ClpP in the mechanism of action of ONC201 and ONC206 in tumor cells.
- |||||||||| Zolinza (vorinostat) / Merck (MSD)
Imipridones and EZH2 inhibitors induce similar changes in cytokines and regulated genes in GBM and DMG while vorinostat potentiates anti-tumor efficacy despite variability in cytokine profiles (Section 14; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_7242;
Shared regulated pathways in U251 included cell cycle arrest, cell adhesion, nervous system development, cell proliferation, negative regulation of proliferation, PERK-mediated unfolded protein response, extracellular matrix organization, regulation of transcription from RNA polymerase II promoter, and cellular response to hypoxia pathways. We conclude that imipridones ONC201, ONC206, and ONC212 which reduce EZH1 and EZH2 proteins share similar cytokine alterations, gene expression targets and actions with EZH2 inhibitors.
- |||||||||| ONC206 / Chimerix, ONC201 / Chimerix
Adaptation to dopamine impairs the anti-cancer effect of ONC201 and ONC206 (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_6807;
Dopamine pre-treatment did not impact changes induced by ONC201 in ATF4, CHOP, DR5, ClpX, clpP, pERK, pAkt and pS6. We are pursuing whether the protective effect of dopamine is due to the agonism of DRD2 or alternative pro-survival mechanisms.
- |||||||||| Imipridones show pre-clinical efficacy in MYCN-amplified and MYCN non-amplified neuroblastoma cell lines (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_4034;
We investigated the anti-tumor effect of three imipridones (ONC201, ONC206, and ONC212), a promising new class of small molecules, in the treatment of neuroblastoma...Cell viability assays with HDAC inhibitors Vorinostat and Panobinostat demonstrated single-agent efficacy in vitro...However, further investigation is needed to determine synergy and mechanisms of synergy when histone deacetylase (HDAC) inhibitors are used in novel combinations with imipridones. Overall, our data reveals promise in imipridone therapy for neuroblastoma, and future studies are proposed to explore potential novel therapeutic combinations in this difficult-to-treat pediatric cancer.
- |||||||||| Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma (Exhibit Hall D) - Nov 16, 2021 - Abstract #SNO2021SNO_885;
Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC-inhibitors and imipridones reduced tumor growth and prolonged host survival more potently than single treatments or vehicle in vivo. Collectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
- |||||||||| temozolomide / Generic mfg.
Preclinical, Journal, Combination therapy: Potent preclinical sensitivity to imipridone-based combination therapies in oncohistone H3K27M-mutant diffuse intrinsic pontine glioma is associated with induction of the integrated stress response, TRAIL death receptor DR5, reduced ClpX and apoptosis. (Pubmed Central) - Oct 22, 2021
We demonstrate synergy between ONC201, ONC206 and ONC212, and targeted therapies with known preclinical activity against DIPG...Six patient-derived DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36) were exposed to imipridones alone or combinations with histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide...Our results suggest increased sensitivity of H3K27M-mutant DIPG cell lines to second generation imipridone therapies, as compared to ONC201. Additionally, there is synergistic cell death with combination of imipridones and panobinostat, romidepsin, or marizomib, which may be further tested in vivo and in clinical trials.
- |||||||||| ONC206 / Chimerix
Enrollment open: NCI-2021-00046: ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (clinicaltrials.gov) - Aug 25, 2021
P1, N=256, Recruiting,
Additionally, there is synergistic cell death with combination of imipridones and panobinostat, romidepsin, or marizomib, which may be further tested in vivo and in clinical trials. Not yet recruiting --> Recruiting
- |||||||||| ONC206 / Chimerix, ONC201 / Chimerix
Journal, PARP Biomarker: A Novel Therapeutic Mechanism of Imipridones ONC201/ONC206 in MYCN-Amplified Neuroblastoma Cells via Differential Expression of Tumorigenic Proteins. (Pubmed Central) - Aug 24, 2021
The protein expression of tumorigenic NMYC, Sox-2, Oct-4, FABP5, and HMGA1 significantly decreased 48 h post-drug treatment, whereas cleaved PARP1/caspase-3 and γH2AX increased 72 h post-drug treatment, compared with vehicle-treated cells in the MYCN-amplified IMR-32 cell line. We are the first to report this novel differential protein expression after ONC201 or ONC206 treatment in human neuroblastoma cells, demonstrating an important multitarget effect which may yield added therapeutic benefits in treating this devastating childhood cancer.
- |||||||||| ONC206 / Chimerix
Clinical, P1 data: CNS posters: Dr Theeler presents "A first-in-human, open label, dose escalation, & food effect Phase I study of oral ONC206 (NCT04541082)" Open NOW for pts w recurrent GBM, gr2/3 gliomas, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas, & more. #asco21 #btsm (Twitter) - Jun 6, 2021
P1
- |||||||||| ONC212 / Chimerix, ONC206 / Chimerix, ONC201 / Chimerix
Journal: Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. (Pubmed Central) - May 21, 2021
A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of central nervous system (CNS) cancers...In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial protease ClpP is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
[VIRTUAL] Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines () - Mar 13, 2021 - Abstract #AACR2021AACR_4503;
Liver cancer cell lines Hep3B and HepG2 were treated with ONC201, ONC206, and ONC212 to determine dose-response effect...Combination treatment effect was also tested between ONC201 and the HDACi vorinostat, PARPi nariparib, and the proteasome inhibitor marizomib...These results suggest that the imipridone family of small molecules is a novel therapy for liver cancer with efficacy as a single agent and in combination with existing targeted agents. Future studies will clarify the mechanisms of synergy and expand the findings into small animal models.
- |||||||||| temozolomide / Generic mfg.
[VIRTUAL] Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG) () - Mar 13, 2021 - Abstract #AACR2021AACR_4371;
We sought to identify synergy between ONC201 or second generation impridones (ONC206 and ONC212), and other chemotherapeutics with known promising pre-clinical activity against DMGs.Seven patient derived H3K27M mutant DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SUDIPG-27, SU-DIPG-29, SU-DIPG-36, SF8628) were grown in culture and exposed to ONC201, ONC206, or ONC212 either as monotherapy or in combination with other FDA approved chemotherapeutics (histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide)...We identified strong synergy between ONC201 and HDAC inhibitors: Panobinostat (CI 0.01) and Romidepsin (CI 0.08), with lesser synergy detected with Entinostat (CI 0.59)...Our results suggest an increased sensitivity of H3K27M DIPG cell lines to second generation imipridones as compared to ONC201. Additionally, we have shown promising synergism between imipridones with Panobinostat or Romidepsin, which should be considered for clinical translation.
- |||||||||| ONC206 / Oncoceutics
[VIRTUAL] Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell response () - Mar 11, 2021 - Abstract #AACR2021AACR_1038;
In addition, ONC206 may also suppresses HGSC growth through activating immune cell response in tumor tissues. Further studies that define the molecular mechanism by which DRD2 modulates the tumor suppressive effect of ONC206 on HGSC cells by suppressing HGSC directly or enhancing anti-tumor immune cell activity will be perform to establish ONC206 as a novel therapeutic agent in treatment of HGSC patients.
- |||||||||| ONC206 / Oncoceutics, ONC201 / Chimerix
[VIRTUAL] Predictive biomarker evaluation and molecular differentiation for imipridones ONC201 and ONC206 () - Mar 11, 2021 - Abstract #AACR2021AACR_340;
Thus, ONC206 is a distinct agent that may be uniquely poised to address tumors that are not addressed by or have developed acquired resistance to ONC201. Our results indicate that for accurate prediction of ONC201 and ONC206 clinical benefit, a curated combinatorial biomarker approach for each tumor type, using diverse detection approaches such as protein expression, genomics, and transcriptomics, may be used in ongoing clinical trials.
- |||||||||| Review, Journal: Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. (Pubmed Central) - Jan 23, 2021
The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.
- |||||||||| ONC206 / Oncoceutics
[VIRTUAL] Preclinical efficacy of the imipridone ONC-206 against medulloblastoma () - Oct 24, 2020 - Abstract #SNO2020SNO_882;
ONC-206 treatment of a transgenic mouse model of Shh MB in vivo significantly reduces tumor growth and doubles survival time in a dose-dependent manner following 2 weeks of therapy. Additional in vivo data will be reported in preparation for a planned Phase I study of ONC-206 in children with malignant brain tumors.
|
