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  • 1
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 7 ( 2019-04-01), p. 2305-2313
    Abstract: Dopamine receptor D2 (DRD2) is a G protein–coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. Experimental Design: The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in & gt;1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. Results: DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. Conclusions: These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi77-vi78
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4874-4874
    Abstract: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor (GPCR) overexpressed in many cancers and its antagonism causes anti-tumor effects. ONC201, founding member of the imipridone class of small molecules, is a DRD2 antagonist in Phase II advanced cancer clinical trials. We evaluated the binding target and anti-tumor activity of ONC206, an ONC201 analog. An orphan small molecule target prediction algorithm revealed that ONC206, like ONC201, antagonizes DRD2. Experimental GPCR profiling using the PathHunter® β-Arrestin assay, confirmed that ONC206 selectively antagonizes D2-like (DRD2/3) but not D1-like (DRD 1/5) dopamine receptors. In this assay, ONC206 possesses a ~10-fold increased potency for DRD2 compared to ONC201 with a Ki of ~320nM with selectivity that was superior to approved antipsychotics. Shotgun mutagenesis across 350 amino acids of DRD2 identified 7 residues critical for ONC206-mediated antagonism of DRD2-induced calcium flux. Consistent with competitive inhibition, mutated residues were within the orthosteric binding site. While 6 mutated residues were also critical for ONC201 activity, one of the mutated residues was unique to ONC206, suggesting differentiated receptor pharmacology. TCGA analysis and immunohistochemistry of patient-derived tissue microarrays revealed DRD2 was overexpressed in neuroblastoma, sarcoma and pheochromocytoma specimens relative to normal tissues. In vitro profiling of ONC206 in the Genomic of Drug Sensitivity in Cancer collection of cell lines revealed broad nanomolar efficacy across most tumor types (GI50 & lt;78-889nM) and ~5 to 20-fold improved potency relative to ONC201. Bone cancer and neuroblastoma were identified as the most ONC206-responsive solid tumor types that were comparatively less responsive to ONC201. Within bone cancer, Ewing's sarcoma (n=16) was most sensitive to ONC206 with nanomolar sensitivity (GI50 168-303nM) that was superior to ONC201. ONC206 was highly efficacious in neuroblastoma (n=35, GI50 87-589nM) including cell lines derived from metastatic sites and with MYCN amplification associated with poor prognosis. In the PC12 rat pheochromocytoma cell line ONC206 (GI50 200nM) was superior to ONC201. ONC206 time-course experiments revealed anti-cancer effects occurring at 48-72 post-treatment, similar to ONC201. In support of a wide therapeutic window, ONC206 reduced the viability of normal human fibroblasts at relatively high doses (GI50 & gt; 5µM). Efficacy evaluation in the MHH-ES-1 Ewing's sarcoma xenograft model demonstrated that ONC206 (100 mg/kg PO every 10 days) causes significant tumor growth inhibition that was comparable to methotrexate (400 mg/kg, IP) while being better tolerated. Thus, imipridone ONC206 acts as a selective antagonist of DRD2/3 at nanomolar concentrations and may address tumor types where the properties of ONC201 do not permit for complete therapeutic engagement in vivo. Citation Format: Varun Vijay Prabhu, Neel Madhukar, Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Neil Charter, Sean Deacon, Alexander VanEngelenburg, Joseph Rucker, Benjamin Doranz, Olivier Elemento, Wolfgang Oster, Martin Stogniew, Joshua Allen. Receptor pharmacology and anti-cancer activity of selective DRD2/3 antagonist imipridone ONC206 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4874.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2792-2792
    Abstract: ONC201 is the lead small molecule of the imipridone class of anti-cancer compounds that is currently being evaluated in phase I/II advanced cancer clinical trials. ONC201 is a highly selective antagonist of the G protein-coupled receptor dopamine receptor D2 (DRD2) that has exhibited promising anti-cancer efficacy and an exceptional safety profile. In the current study, we evaluated the influence of the DRD2 pathway on the responsiveness of tumors to ONC201 in preclinical and clinical studies. In vitro and in vivo studies have previously demonstrated robust ONC201 efficacy in glioblastoma (Allen et al 2013) and lymphoma (Ishizawa et al 2016) models. ONC201 Phase I trials have also revealed evidence of clinical benefit in endometrial cancer (Stein et al 2016). In vitro efficacy profiling of ONC201 in the Genomic of Drug Sensitivity in Cancer (GDSC) collection of cell lines confirmed broad-spectrum anti-cancer efficacy with particularly high sensitivity in lymphoma, neuroblastoma, endometrial and brain cancer. DRD2 is overexpressed in many cancers and DRD2 antagonism kills cancer cells via the same signaling pathways that are altered in response to ONC201. Results from the Project Achilles screen indicate that anti-cancer effects of DRD2 knockdown in various tumor types correlated with overall ONC201 efficacy. In particular, we noted that lymphoma cells are highly sensitive to DRD2 knockdown- a tumor type where ONC201 performs well. Gene expression analysis of samples in the Cancer Genome Atlas (TCGA) revealed high DRD2 expression in ONC201-sensitive tumor types, such as lymphoma and glioblastoma, and that high expression of DRD2 in glioma was associated with a poor prognosis. High DRD2 expression was also observed in neuroendocrine prostate cancer relative to other prostate cancer subtypes. In immunohistochemistry analyses of patient-derived tumor tissue microarrays, DRD2 overexpression was particularly noted in endometrial cancer, neuroblastoma and pheochromocytoma relative to normal tissues. The anti-cancer activity of ONC201 in pheochromocytoma and neuroendocrine prostate cancer was confirmed in cell viability assays. In ONC201-treated patients, ELISA was used to quantitate serum prolactin levels, a clinical biomarker of DRD2 antagonism. A 2-fold mean induction of prolactin, was detected in the serum of ONC201-treated patients, in accordance with physiological DRD2 antagonism. Interestingly, expression of DRD5 (a D1-like dopamine receptor), which counteracts DRD2 signaling, was significantly negatively correlated with ONC201 in vitro potency in the NCI60 and GDSC dataset (P & lt;.05). Furthermore, a missense DRD5 mutation was identified in cancer cells with acquired resistance to ONC201. In conclusion, the DRD2 pathway is expressed in ONC201-sensiive tumors and may provide biomarkers of response. Citation Format: Neel Madhukar, Varun Vijay Prabhu, Etienne Dardenne, Faye Doherty, Alexander VanEngelenburg, Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Wolfgang Oster, Wafik El-Deiry, Mark Stein, David Rickman, Joshua Allen, Olivier Elemento. The small molecule imipridone ONC201 is active in tumor types with dysregulation of the DRD2 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2017-2792
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4147A-4147A
    Abstract: DRD2 is a G protein-coupled receptor (GPCR) that is overexpressed in many cancers, controls an array of pro-survival signaling pathways, and its antagonism causes anti-cancer effects. ONC201, the founding member of the imipridone class of anti-cancer compounds, is a small molecule DRD2 antagonist that is in Phase I/II advanced cancer clinical trials. In this study, we evaluated the binding target and antitumor activity of ONC206, a chemical analogue of ONC201. An orphan small molecule target prediction algorithm revealed that ONC206, like ONC201, antagonizes DRD2. Experimental GPCR profiling using the PathHunter® β-Arrestin assay, determined that ONC206 selectively antagonizes the D2-like (DRD2/3/4), but not the D1-like (DRD 1/5), subfamily of dopamine receptors. ONC206 possesses a ~10-fold increased affinity for DRD2 compared to ONC201 with a Ki of ~320nM with selectivity that was superior to approved antipsychotics. The increased association rate for the ONC206-DRD2 interaction was responsible for the increased affinity, whereas the dissociation rate was similar to ONC201 and atypical antipsychotics that are well tolerated. TCGA analysis and immunohistochemistry of patient-derived tissue microarrays revealed DRD2 was overexpressed in neuroblastoma, sarcoma and pheochromocytoma specimens relative to normal tissues. In vitro efficacy profiling of ONC206 in the Genomic of Drug Sensitivity in Cancer collection of cell lines revealed broad efficacy across most tumor types (GI50 & lt;78-889nM). Bone cancer and neuroblastoma were identified as the most ONC206-responsive solid tumor types that were comparatively less responsive to ONC201. Within bone cancer cell lines, Ewing’s sarcoma (n=16) was the most sensitive to ONC206 with nanomolar sensitivity (GI50 168-303nM) that was superior to ONC201. ONC206 was highly efficacious in neuroblastoma (n=35, GI50 87-589nM) including cell lines derived from metastatic sites and with MYCN amplification associated with poor prognosis. In the PC12 rat pheochromocytoma cell line ONC206 (GI50 200nM) was superior to ONC201. ONC206 time-course experiments revealed anti-cancer effects occurring at 48-72 post-treatment, similar to ONC201. In support of a wide therapeutic window, ONC206 reduced the viability of normal fibroblasts (HFF-1) at relatively high doses (GI50 & gt; 5µM). Efficacy evaluations in MHH-ES-1 athymic nude mice xenografts demonstrated that ONC206 (100 mg/kg PO every 10 days) causes significant tumor growth inhibition that was comparable to methotrexate (400 mg/kg, IP) while being better tolerated. In summary, ONC206 is an imipridone that acts as a selective antagonist of DRD2 at nanomolar concentrations and has broad-spectrum anti-tumor activity. ONC206 may address tumor types where the properties of ONC201 do not permit for complete therapeutic engagement in vivo. Citation Format: Varun Vijay Prabhu, Neel Madhukar, Jessica Wagner, Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Neil Charter, Sean Deacon, Alexander VanEngelenburg, Olivier Elemento, Wafik El-Deiry, Martin Stogniew, Wolfgang Oster, Joshua Allen. Potent anti-cancer activity of the imipridone ONC206: A selective dopamine D2-like receptor antagonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4147A. doi:10.1158/1538-7445.AM2017-4147A
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 6
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 19, No. suppl_6 ( 2017-11-06), p. vi60-vi60
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2094060-9
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  • 7
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi88-vi88
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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  • 8
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A060-A060
    Abstract: Background: ONC201, an imipridone that is a selective antagonist of the G protein-coupled receptors dopamine receptor D2 (DRD2) and D3 (DRD3), has exhibited biologic activity and an exceptional safety profile in a phase II study in bevacizumab-naïve recurrent glioblastoma (Arrillaga et a.l, 2017). Single-agent ONC201 efficacy has been observed in preclinical glioblastoma models in addition to robust penetrance of the blood-brain barrier (Allen et al., 2013). DRD2 antagonism induces tumor cell apoptosis via the same signaling pathways affected by ONC201. In addition, DRD2 is expressed on NK and other immune cells and DRD2 antagonism can induce their activation. Methods: Cell viability assays were performed with ONC201 in & gt;1000 Genomic of Drug Sensitivity in Cancer (GDSC) cell lines and NCI60. Immunohistochemistry staining of DRD2/DRD5 was performed in glioblastoma tissue microarrays and archival tumor tissues. Whole exome sequencing was performed in RKO cells with acquired resistance to ONC201. DRD5 wild-type and mutant constructs were generated for overexpression studies. ELISA was used to quantitate serum prolactin and immune effector (perforin) levels. Intratumoral drug concentrations were evaluated by LC-MS assays conducted on glioblastoma tissue resected from patients following the second dose of 625mg ONC201. Results: Evaluation of ONC201 in GDSC cell lines confirmed broad anticancer efficacy with high sensitivity (~1-3 µM) in human brain cancer. The Cancer Genome Atlas (TCGA) revealed that DRD2 is highly expressed in glioblastoma relative to other dopamine receptors and that genetic aberrations are rare. High expression of DRD2 occurred in primary, rather than secondary, glioblastoma and was associated with a poor prognosis. Immunohistochemistry of tissue microarrays revealed DRD2 overexpression in glioblastoma relative to normal brain. A linear correlation between DRD2 mRNA and ONC201 GI50 was observed among glioblastoma cell lines in the NCI60 panel. Interestingly, expression of DRD5, a D1-like dopamine receptor that counteracts DRD2 signaling, was significantly inversely correlated with ONC201 potency in the NCI60 and GDSC datasets (P & lt;.05). Furthermore, a missense DRD5 mutation was identified in cancer cells with acquired resistance to ONC201. Resistance could be recapitulated with overexpression of the mutant or wild-type DRD5 gene. A significant induction of serum prolactin, a surrogate biomarker of target engagement, was detected upon ONC201 administration to recurrent glioblastoma patients. Intratumoral drug concentrations surpassed therapeutic levels, ranging from ~0.6-10µM at 24 hours post-dose. Immune effector levels in the serum correlated with the kinetics of a durable objective response observed in a patient with an H3.3 K27M glioma. Among the 15 available archival tumor tissue specimens, all had expression of DRD2 and 8/17 patients had low expression of DRD5. Patients with PFS & gt;5 month had no detectable expression of DRD5, unlike those with PFS & lt;5 months. In addition, 4/8 DRD2+DRD5- and 0/7 DRD2+DRD5+ patients are still alive with a median follow-up of 47.4 weeks. Conclusion: The dopamine receptor pathway is a novel therapeutic target that is dysregulated in glioblastoma and provides predictive and pharmacodynamic biomarkers of tumor sensitivity to ONC201. Citation Format: Varun Vijay Prabhu, Neel Madhukar, C. Leah B. Kline, Rohinton Tarapore, Wafik El-Deiry, Olivier Elemento, Faye Doherty, Alexander VanEngelenburg, Jessica Durrant, Andrew Zloza, Cyril Benes, Isabel Arrillaga, Wolfgang Oster, Joshua E. Allen. Targeting DRD2 dysregulation in recurrent glioblastoma with imipridone ONC201: predictive and pharmacodynamic clinical biomarker analyses [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A060.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    SSG: 12
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3857-3857
    Abstract: D2-like dopamine receptors (DRD2/3/4) are G protein-coupled receptors (GPCRs) that are overexpressed in glioblastoma (GBM) and their antagonism induces tumor cell apoptosis. We describe the first selective DRD2/3 antagonist for neuro-oncology using computational, receptor pharmacology, biochemical and clinical studies. Consistent with an in-silico prediction and in contrast to antipsychotics that target several dopamine receptors and other GPCRs, β-arrestin recruitment and cAMP assays determined that ONC201 is a selective DRD2/3 antagonist. Schild analyses and radioligand competition assays revealed competitive and non-competitive DRD2 antagonism with a potency (2-3 µM) that is consistent with anticancer activity and driven by an unusually slow association rate. Proof-of-concept studies show that selective DRD2 inhibition induces superior anti-cancer efficacy relative to pan-targeting of the dopamine receptor family. In accordance with superior selectivity, ONC201 also exhibited a wider therapeutic window compared to antipsychotics. Shotgun mutagenesis across 350 amino acids of DRD2 identified 8 residues that are critical for ONC201-mediated DRD2 antagonism. Consistent with competitive inhibition, several mutated residues were within the orthosteric binding site. However, distal residues were identified that were not involved in DRD2 antagonism by antipsychotics and may explain the selectivity and non-competitive antagonism of ONC201. In vitro and in vivo studies have previously demonstrated single agent ONC201 efficacy in GBM models (Allen et al 2013). Analyses of The Cancer Genome Atlas and tissue microarrays revealed high DRD2 expression relative to other dopamine receptors, correlation with poor prognosis and high DRD2 expression in primary rather than secondary GBM. A linear correlation between DRD2 mRNA and ONC201 GI50 was observed among GBM cell lines in the NCI60 panel. Interestingly expression of DRD5, a D1-like dopamine receptor that counteracts DRD2 signaling, was significantly inversely correlated with ONC201 potency in the NCI60 dataset (P & lt;.05). Furthermore, a de novo missense DRD5 mutation was identified in cancer cells with acquired resistance to ONC201, and overexpression of the mutant construct could recapitulate resistance. ONC201 exhibited biological activity in a phase II recurrent GBM study, including tumor regressions (Arrillaga et al, 2017). Among the 15 available archival patient tumor specimens from the first cohort of this trial, all had DRD2 expression and 8 had low DRD5 expression that was associated with superior progression-free and overall survival, with 4/8 DRD5- and 0/7 DRD5+ patients alive after 15 months (P=0.012). Thus, ONC201 possesses unique receptor pharmacology as the first selective DRD2/3 antagonist for clinical neuro-oncology that has exhibited clinical activity in biomarker-defined recurrent high grade glioma patients. Citation Format: Varun Vijay Prabhu, Neel Madhukar, C. Leah B. Kline, Rohinton Tarapore, Wafik S. El-Deiry, Joseph Rucker, Benjamin Doranz, Faye Doherty, Alexander VanEngelenburg, Jessica Durrant, Cyril Benes, Sean Deacon, Neil Charter, R. Benjamin Free, Wolfgang Oster, David Sibley, Isabel Arrillaga, Olivier Elemento, Joshua E. Allen. Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3857.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3877-3877
    Abstract: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor that is overexpressed and critical for survival in several cancers. ONC201, an imipridone small molecule, is a DRD2/3 antagonist in Phase II advanced cancer clinical trials with a compelling safety and efficacy profile. We evaluated the binding target, anti-tumor activity, biodistribution and safety of ONC206, a chemical derivative of ONC201 with the same imipridone core structure. GPCR profiling with β-Arrestin recruitment revealed that ONC206 selectively antagonizes dopamine receptors DRD2 and DRD3. ONC206 exhibited a Ki of ~320nM for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. While 6 mutated residues were also critical for ONC201-mediated antagonism, the impact and magnitude of different mutants varied between the two compounds and one of the allosteric residues was unique to ONC206. In vitro profiling of ONC206 in & gt;1000 GDSC cancer cell lines demonstrated broad nanomolar efficacy (GI50 & lt;78-889nM). TCGA and tissue microarrays analyses revealed that malignant DRD2 expression was highest in pheochromocytoma, high grade gliomas, neuroblastoma, medulloblastoma, Ewing’s sarcoma and cholangiocarcinoma. Accordingly, ONC206 demonstrated nanomolar in vitro sensitivity in these tumor types. Similar to ONC201, a DRD2+/DRD5- RNA expression signature in the GDSC panel predicted significantly enhanced ONC206 sensitivity. ONC206 reduced the viability of normal human fibroblasts at micromolar doses (GI50 & gt; 5µM), suggesting a wide therapeutic window. Robust inhibition of tumor growth without body weight loss was observed in HuCCT1 cholangiocarcinoma and MHH-ES-1 Ewing’s sarcoma subcutaneous xenografts with 50-100 mg/kg oral ONC206 weekly or every 2 weeks. Biodistribution studies in Sprague-Dawley rats revealed a ~12 µM plasma Cmax with a half-life of ~6 hours upon a single oral dose of 50 mg/kg. Additionally, 5-10 fold higher ONC206 concentrations were observed in adrenal gland, bile duct, brain and bone marrow relative to plasma concentrations. GLP toxicology studies with weekly oral ONC206 in Sprague-Dawley rats and beagle dogs at doses above or equivalent to efficacious doses revealed no dose-limiting toxicities. In both species, observations at the highest dose were mild and reversible. The no observed adverse event level (NOAEL) was ≥ 16.7 mg/kg in dogs and ≥ 50 mg/kg in rats, which both correspond to a human dose of approximately 500 mg assuming standard allometric scaling. These results provide rationale for a 50 mg starting ONC206 dose in dose escalation clinical trials in patients with DRD2-dysregulated tumors. Citation Format: Varun V. Prabhu, Abed Rahman Kawakibi, Neel Madhukar, Mathew J. Garnett, Ultan McDermott, Cyril H. Benes, Lakshmi Anantharaman, Neil Charter, Sean Deacon, Alexander VanEngelenburg, Joseph B. Rucker, Benjamin J. Doranz, Jessica Rusert, Robert Wechsler-Reya, Olivier Elemento, Martin Stogniew, Wolfgang Oster, Sharon DeMorrow, R. Benjamin Free, David R. Sibley, Joshua E. Allen. IND-enabling characterization of DRD2/3 imipridone antagonist ONC206 for oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3877.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 410466-3
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