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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi77-vi78
    Description: ONC201 is the first selective antagonist of dopamine receptor D2 (DRD2) and D3 (DRD3) for clinical oncology that has exhibited preliminary clinical activity in high grade gliomas. We investigated DRD2 dysregulation in glioma and its role in ONC201 efficacy. Investigating CRISPR screens across a spectrum of cancer revealed that glioma cell lines had the highest DRD2 gene essentiality scores, indicating that glioma is a tumor type with the most vulnerability to DRD2 antagonism. Investigation of TCGA revealed that DRD2 is highly expressed in glioblastoma relative to other dopamine receptor family members and is associated with a relatively poor clinical prognosis. Tissue microarray analysis confirmed DRD2 overexpression in glioblastoma relative to normal brain. A linear correlation between DRD2 mRNA and ONC201 GI50 was observed among NCI60 glioblastoma cell lines. Similarly, we found a significant concordance between a cell line’s sensitivity to ONC201 within the Genomics of Drug Sensitivity in Cancer (GDSC) panel and its DRD2 gene essentiality score. Next, we ranked the relative contribution of each dopamine receptor to ONC201 efficacy using a bioinformatics approach based on a generalized linear model. We found that the strongest negative contributor was DRD2 – where a negative contribution denotes a decreased IC50 value as expression increases. Interestingly, DRD5, a D1-like dopamine receptor that counteracts DRD2 signaling, was measured as having the highest positive score – indicating that low expression of DRD5 was correlated with ONC201 efficacy. DRD5 expression was significantly inversely correlated with ONC201 potency in the NCI60 and GDSC datasets. Furthermore, a missense DRD5 mutation was identified in tumor cells with acquired resistance to ONC201. Resistance could be recapitulated with overexpression of the mutant or wild-type DRD5 gene. In conclusion, DRD2 dysregulation and DRD5 expression predict preclinical ONC201 glioma sensitivity that may be used to identify additional settings for clinical evaluation.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
  • 3
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 17 December 2018
    Description: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anti-cancer 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. The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in 〉1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. Immunohistochemistry staining of DRD2/DRD5 was performed in 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. 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 recurrent glioblastoma patients treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 4
    Language: English
    In: Science signaling, 16 February 2016, Vol.9(415), pp.ra18
    Description: ONC201 (also called TIC10) is a small molecule that inactivates the cell proliferation- and cell survival-promoting kinases Akt and ERK and induces cell death through the proapoptotic protein TRAIL. ONC201 is currently in early-phase clinical testing for various malignancies. We found through gene expression and protein analyses that ONC201 triggered an increase in TRAIL abundance and cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5. ATF4 was not activated in ONC201-resistant cancer cells, and in ONC201-sensitive cells, knockdown of ATF4 or CHOP partially abrogated ONC201-induced cytotoxicity and diminished the ONC201-stimulated increase in DR5 abundance. The activation of ATF4 in response to ONC201 required the kinases HRI and PKR, which phosphorylate and activate the translation initiation factor eIF2α. ONC201 rapidly triggered cell cycle arrest, which was associated with decreased abundance of cyclin D1, decreased activity of the kinase complex mTORC1, and dephosphorylation of the retinoblastoma (Rb) protein. The abundance of X-linked inhibitor of apoptosis protein (XIAP) negatively correlated with the extent of apoptosis in response to ONC201. These effects of ONC201 were independent of whether cancer cells had normal or mutant p53. Thus, ONC201 induces cell death through the coordinated induction of TRAIL by an ISR pathway.
    Keywords: Activating Transcription Factor 4 -- Metabolism ; Heterocyclic Compounds, 4 or More Rings -- Pharmacology ; Neoplasms, Experimental -- Drug Therapy ; Signal Transduction -- Drug Effects ; Tumor Suppressor Protein P53 -- Metabolism ; Eif-2 Kinase -- Metabolism
    ISSN: 19450877
    E-ISSN: 1937-9145
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  • 5
    Language: English
    In: Cell Cycle, 16 February 2018, Vol.17(4), pp.468-478
    Description: ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
    Keywords: Onc201 ; Multiple Myeloma ; Lymphoma ; Imipridone ; Leukemia ; Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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  • 6
    Language: English
    In: Allen, J. E., C. L. B. Kline, V. V. Prabhu, J. Wagner, J. Ishizawa, N. Madhukar, A. Lev, et al. 2016. “Discovery and clinical introduction of first-in-class imipridone ONC201.” Oncotarget 7 (45): 74380-74392. doi:10.18632/oncotarget.11814. http://dx.doi.org/10.18632/oncotarget.11814.
    Description: ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.
    Keywords: Onc201 ; Tic10 ; Integrated Stress Response ; Atf4 ; Drd2
    ISSN: 19492553
    E-ISSN: 19492553
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  • 7
    Description: ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and...
    Keywords: Biophysics ; Biochemistry ; Space Science ; Medicine ; Cell Biology ; Genetics ; Molecular Biology ; Pharmacology ; Biotechnology ; Chemical Sciences Not Elsewhere Classified ; Cancer ; Hematology ; Infectious Diseases ; Virology
    Source: DataCite
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  • 8
    Description: ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and...
    Keywords: Biophysics ; Biochemistry ; Space Science ; Medicine ; Cell Biology ; Genetics ; Molecular Biology ; Pharmacology ; Biotechnology ; Chemical Sciences Not Elsewhere Classified ; Cancer ; Hematology ; Infectious Diseases ; Virology
    Source: DataCite
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  • 9
    Language: English
    In: The Journal of clinical investigation, 01 June 2018, Vol.128(6), pp.2325-2338
    Description: ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.
    Keywords: Apoptosis Pathways ; Cancer Immunotherapy ; Nk Cells ; Oncology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 10
    In: Neuro-Oncology, 2017, Vol. 19(suppl6), pp.vi60-vi60
    Description: ONC201, an imipridone that is a selective antagonist of the G protein-coupled receptors dopamine receptor D2 (DRD2) and D3 (DRD3), has exhibited tumor shrinkage and an exceptional safety profile in a phase II recurrent glioblastoma clinical trial (Arrillaga et al, 2017). In vitro and in vivo studies have previously demonstrated single agent ONC201 efficacy in glioblastoma models (Allen et al 2013). In vitro efficacy profiling of ONC201 in the Genomic of Drug Sensitivity in Cancer (GDSC) collection of cell lines confirmed broad anti-cancer efficacy with high sensitivity in human brain cancer cell lines. DRD2 is overexpressed in glioblastoma and DRD2 antagonism induces tumor cell apoptosis via the same signaling pathways that respond to ONC201. Investigation of The Cancer Genome Atlas (TCGA) revealed that DRD2 is highly expressed in glioblastoma relative to other dopamine receptor family members and that genetic aberrations were rare. High expression of DRD2 occurred in primary, rather than secondary, glioblastoma and was associated with a poor prognosis. Immunohistochemistry analyses 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. A significant induction of serum prolactin, a surrogate biomarker of target engagement, was detected in ONC201-treated glioblastoma patients. 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 〈.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 DRD5 gene or, to a lesser extent, with the wild-type gene. In conclusion, the DRD2 pathway is a therapeutic target that is dysregulated in glioblastoma and contains biomarkers of tumor sensitivity to ONC201 that are under clinical evaluation.
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press
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