Publications
RESEARCH ARTICLES
Stein et al. Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration. Journal for ImmunoTherapy of Cancer, 2019.
Arrillaga-Romany et al. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma Oncotarget, 2017.
Hall et al. First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M-mutant pediatric diffuse intrinsic pontine glioma: a case report. Journal of Neurosurgery, 2019.
Chi et al. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201 Journal of Neuro-Oncology, 2019.
Romaguera et al. Integrated stress response and immune cell infiltration in an ibrutinib-refractory mantle cell lymphoma patient following ONC201 treatment British Journal of Haematology, 2018.
Stein et al. First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors Clinical Cancer Research 2017 Mar 22 doi:10.1158/1078-0432.CCR-16-2658.
Madhukar et al. A Bayesian machine learning approach for drug target identification using diverse data types. Nat Commun 10, 5221 (2019) doi:10.1038/s41467-019-12928-6
Sibley et al. Characterization of the novel anti-cancer therapeutic ONC201 and related analogs as non-competitive antagonists of the D2 dopamine receptor. The FASEB Journal Vol. 32, No. 1_supplement, April 2018. Abstract Number:827.10
Kline et al. Role of Dopamine Receptors in the Anticancer Activity of ONC201 Neoplasia (2017) doi: 10.1016/j.neo.2017.10.002
Klien et al. From TRAIL to ONC201: Case Study on the Safety Benefit of Developing Targeted Agents Against Cancer‐selective Pathways. Early Drug Development: Bringing a Preclinical Candidate to the Clinic, Volume 1. https://doi.org/10.1002/9783527801756.ch23
Siegelin et al. Metabolic Reprogramming by Dual AKT/ERK Inhibition Through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. CCR (2018). DOI: 10.1158/1078-0432.CCR-18-1040
Prabhu et al. Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism. CCR (2018). doi: 10.1158/1078-0432.CCR-18-2572
Kline et al. eIF2α kinases, HRI and PKR, signal ATF4 activation that is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201. Science Signaling 9 (2016) DOI: 10.1126/scisignal.aac4374
Ishizawa et al. ATF4 induction through an atypical integrated stress response to ONC201 induces p53-independent apoptosis in hematological malignancies. Science Signaling 9 (2016) DOI: 10.1126/scisignal.aac4380
Yuan et al. ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells Oncotarget. 2017; 8:21626-21638. doi: 10.18632/oncotarget.15451
Allen et al. Discovery and clinical introduction of first-in-class imipridone ONC201 Oncotarget. 2016 Sep 1. doi: 10.18632/oncotarget.11814
Wagner et al. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity. Oncotarget, 30 December 2014: Vol 5, Issue 24, p12728-37.
Allen et al. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Molecular Cancer. 2015 May 1;14(1):99.
Allen et al. First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent. PLoS One. 2015 Nov 18;10(11):e0143082
Allen et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
Science Translational Medicine, 6 February 2013: Vol 5, Issue 171, p171ra17.
Wagner et al. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment The Journal of Clinical Investigation (JCI) 2018 Mar 13 doi:10.1172/JCI96711.
Ishizawa et al. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell (2019). DOI: 10.1016/j.ccell.2019.03.014
Graves et al. Mitochondrial Protease ClpP is a Target fir the Anticancer Compounds ONC201 and Related Analogues. ACS Chem. Biol. (2019). DOI 10.1021/acschembio.9b00222
Siegelin et al. Metabolic Reprogramming by Dual AKT/ERK Inhibition Through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. CCR (2018). DOI: 10.1158/1078-0432.CCR-18-1040
Karpel-Massler et al. TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo
Oncotarget (2015).
Karpel-Massler et al. TIC10/ONC201—a potential therapeutic in glioblastoma
Translational Cancer Research (2017) doi: 10.21037/tcr.2017.10.51
Ralff et al. ONC201: a new treatment option being tested clinically for recurrent glioblastoma
Translational Cancer Research (2017); Vol. 6 (7) doi: 10.21037/tcr.2017.10.03
Greer et al. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget (2018)
Hayes-Jordan et al. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor; Neoplasia (2018)
Lev et al. ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer; Molecular Cancer Research (2018)
Wagner et al. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms; Journal of Experimental & Clinical Cancer Research (2018).
Jin et al. mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity; Biochem Biophys Res Commun (2016) doi:10.1016/j.bbrc.2016.08.126.
Zhang et al. The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent; Biochem Biophys Res Commun. (2016).
Feng et al. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells; PLOS One (2016).
Ralff et al. ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms; Molecular Cancer Therapeutics (2017) doi: 10.1158/1535-7163.MCT-17-0121.
Bai et al. Identification of DNA-PKcs as a primary resistance factor of TIC10 (ONC201) in hepatocellular carcinoma cells; Oncotarget (2017) doi: 10.18632/oncotarget.16073.
Allen et al. Genetic and pharmacological screens converge in identifying FLIP, BCL2 and IAP proteins as key regulators of sensitivity to the TRAIL-inducing anti-cancer agent ONC201/TIC10; Cancer Research (2015) [Epub ahead of print].
Fang et al. ONC201 demonstrates anti-tumorigenic and anti-metastatic activity in uterine serous carcinoma in vitro; American Journal of Cancer Research. 2018;8(8):1551-1563.
Talekar et al. ONC201 Induces Cell Death in Pediatric non-Hodgkin’s Lymphoma Cells.
Cell Cycle 2015 Aug 3;14(15):2422-8.
Xi et al. ONC201 selectively induces apoptosis in cutaneous T-cell lymphoma cells via activating pro-apoptotic integrated stress response and inactivating JAK/STAT and NF-κB pathways
Oncotarget 2017 June 27 doi: 10.18632/oncotarget.18688
Tu et al. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma
Neoplasia (2017) 19(10) doi: 10.1016/j.neo.2017.07.009
Prabhu et al. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies
Cell Cycle (2017) doi: 10.1080/15384101.2017.1403689
Chari et al. Imipridone ONC201: Combination therapy in hematologic malignancies.
Cell Cycle. 2018 Jun 21. doi: 10.1080/15384101.2018.1490861.
Edwards et al. ONC201 shows promise in AML treatment.
Cell Cycle. 2018;17(3):277. doi: 10.1080/15384101.2017.1421035.
Prabhu et al. Small molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Research, 2015 Feb 20. pii: canres.3451.2013. [Epub ahead of print].
Prabhu et al. Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors. PLoS ONE (2017) 12(8): e0180541. doi: 10.1371/journal.pone.0180541
Wagner et al. Preclinical evaluation of the imipridone family, analogues of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212
Cell Cycle Online doi: 10.1080/15384101.2017.1325046
Lev et al. Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP
Oncotarget (2017) Sept. 12 doi: 10.18632/oncotarget.20819
Chi Identification of more potent imipridones, a new class of anti-cancer agents.
Cell Cycle. 2017 Jul 27:0. doi: 10.1080/15384101.2017.1355171. [Epub ahead of print]
Anderson et. al Imipridone Family on Successful TRAIL
Cell Cycle News and Views doi: 10.1080/15384101.2017.134523
Ishida et. al Metabolic Reprogramming by Dual AKT/ERK Inhibition Through Imipridones Elicits Unique Vulnerabilities in Glioblastoma
AACR doi: 10.1158/1078-0432.CCR-18-1040
CONFERENCE ABSTRACTS
ONC201:
1286 / 1 – ONC201 inhibits RET and IGFBP2 signaling through ATF4 mediated- Integrated stress response in medullary thyroid cancer
249 / 12 – Combination of ONC201 with radiation exhibits synergistic efficacy in high grade gliomas and other advanced cancers
5183 / 1 – ONC201 induces acetylation of histone binding within the p21 (CDKN1A) gene promoter
2664 / 18 – Differential activation of the integrated stress response correlates with anti-tumor activity of imipridones ONC201 and ONC206 in pediatric sarcomas
4808 / 22 – Preclinical studies of the combination of ONC201, radiotherapy and Temozolomide against GBM, DIPG and ATRT cell lines
2928 / 16 – New insight into signaling contexts for the administration of the imipridone ONC201 to prostate cancer cells
364 / 25 – The dopamine receptor D2 antagonist ONC201 has anti-tumorigenic activity in obesity-driven epithelial ovarian cancer
258 / 2 – Recombinant human TRAIL or a DR5 agonistic antibody convert the response of non-triple negative breast cancer cells to ONC201 from anti-proliferative to apoptotic
262 / 6 – Anti-tumorigenic effect of ONC201 is enhanced by combination treatment with TRAIL or a DR5 agonist in endometrial cancer in vitroNeuro-Tumor Club – Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201
Imipridone GPCR SAR:
2749 / 1 – Defining structure activity relationships for GPCR engagement and anti-cancer efficacy of imipridone small molecules
ONC206:
3877 / 27 – IND-enabling characterization of DRD2/3 imipridone antagonist ONC206 for oncology
Oral Talks:
2720 – Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality
Neuro-Tumor Club – IND-enabling characterization of DRD2/3 imipridone antagonist ONC206 for oncology
ONC201 Clinical Translation:
(3857) Prabhu et al. Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201, April 17, 2018, 8:00 AM
(4872) Proudfit et al. ONC201 induction of apoptosis in hPheo1 cell line supports use of this oral agent in ongoing phase 2 clinical trial against neuroendocrine tumors, April 17, 2018, 1:00 PM
(5568) Tarapore et al. Clinical immunostimulatory activity of imipridone ONC201, a selective DRD2 antagonist, in advanced solid tumor patients, April 18, 2018, 8:00 AM
ONC201 Preclinical Single Agent and Combinatorial Activity
(839) Amoroso et al. Treatment and signaling contexts for the application of the imipridone ONC201 to prostate cancer cells, April 15, 2018, 1:00 PM
(LB-082) Ralff et al. ONC201 sensitizes resistant breast cancer cells to TRAIL through death receptor 5 upregulation, April 16, 2018, 8:00 AM – 12:00 PM
(2933) Zhou et al. Synergistic antitumor effect of ONC201 in combination with radiation therapy, April 16, 2018, 1:00 PM
(2765) Jhawar et al. Combination ONC201 and radiation therapy in the treatment of breast cancer, April 16, 2018, 1:00 PM
Analogs (ONC206 and ONC212):
(4874) Prabhu et al. Receptor pharmacology and anti-cancer activity of selective DRD2/3 antagonist imipridone ONC206, April 17, 2018, 1:00 PM
(4957) The novel imipridone ONC212 highly synergizes with the BCL-2 inhibitor ABT-199 in AML and activates orphan receptor GPR132 April 17, 2018, 3:35 PM – Oral Presentation
Madhukar et al. Differentiated receptor pharmacology of imipridone ONC201: the first DRD2 antagonist in clinical development for oncology 2017 AACR April 1-5 Washington DC
Madhukar et al. The small molecule imipridone ONC201 is active in tumor types with dysregulation of the DRD2 pathway 2017 AACR April 1-5 Washington DC
Klein et al. Antagonism of D2-like dopamine receptors plays a role in ONC201’s anti-cancer effects 2017 AACR April 1-5 Washington DC
Lim et al. Preclinical evaluation of imipridone ONC201 in triple negative breast cancer identifies predictive biomarkers and combinatorial opportunities 2017 AACR April 1-5 Washington DC
Prabhu et al. Potent anti-cancer effects of selective GPR132/G2A agonist imipridone ONC212 in leukemia and lymphoma 2017 AACR April 1-5 Washington DC
Prabhu et al. Potent anti-cancer activity of the imipridone ONC206: A selective dopamine D2-like receptor antagonist 2017 AACR April 1-5 Washington DC
Wagner et al. Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212 2017 AACR April 1-5 Washington DC
Lev et al. Anti-cancer efficacy of imipridones in pancreatic cancer: single agent ONC212 or combination of ONC201 with IGF1-R inhibition 2017 AACR April 1-5 Washington DC
Tu et al. Imipridone ONC201 efficacy in refractory multiple myeloma via Erk1/2 inhibition and pro-apoptotic Bim upregulation: Single agent and combinatorial approaches 2017 AACR April 1-5 Washington DC
Wagner et al. Imipridone ONC201 promotes intra-tumoral accumulation of CD3+/NK+ cells that contribute to its anti-tumor efficacy 2017 AACR April 1-5 Washington DC
Greer et al. ONC201 kills breast cancer cells by inhibiting mitochondrial respiration 2017 AACR April 1-5 Washington DC
Amoroso et al. Modulating the UPR using the imipridone ONC201 to change the impact of radiation on prostate cancer cells. 2017 AACR April 1-5 Washington DC
Lev et al. ONC201 targets AR and AR-V7 signaling pathways, reduces PSA and synergizes with everolimus in castration resistant prostate cancer 2017 AACR April 1-5 Washington DC
Baumeister et al. ONC201 efficacy in BRCA-deficient cancer cells and synergy with PARP inhibitors in glioblastoma, breast, prostate, and ovarian cancers 2017 AACR April 1-5 Washington DC
Wagner et al. Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo 2017 AACR April 1-5 Washington DC
Madhukar et al. D2-like dopamine receptor antagonism by ONC201 identified by confluence of computational, receptor binding, and clinical studies 2016 AACR –Apr. 17 – Apr. 20; New Orleans, LA.
Lev, El-Deiry et al. ONC201 induces cell death in androgen receptor positive prostate cancer cells and shows synergistic effect with anti-prostate cancer drugs 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Prabhu et al. ONC201 targets cancer stem cells in colorectal, prostate and glioblastoma multiforme tumors via modulation of stem cell-related gene expression 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Tarapore at al. ONC201 sensitivity profiling indicates pronounced sensitivity in lymphoid, prostate, colon and brain tumors 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Lev, El-Deiry et al. ONC212 exhibits increased cytotoxicity relative to ONC201 in a subset of human pancreatic cancer cell lines 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Wagner, El- Deiry et al. Structure-activity relationships and mechanistic analysis of analogues of the clinical-stage anti-cancer small molecule ONC201 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Wagner, El-Deiry et al. Intra-tumoral accumulation of NK1.1/CD3+ cells and anti-metastisis effects of dose-intensified ONC201 in tumor-bearing mice 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Baumeister, El-Deiry et al. ONC201 induces cell death in triple negative, BRCA1-deficient and non-triple negative breast cancer cells 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Kline, El-Deiry et al. ONC201 anti-cancer effects against solid tumors are mediated through elF2α kinases HRI and PKR but are PERK-independent 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Baumeister, El-Deiry et al. Novel small molecule ONC201 induces cell death and targets chemotherapy-resistant cancer stem-like cells in triple negative breast cancer 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Wagner, El-Deiry et al. Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo 2016 AACR — Apr. 17 – Apr. 20; New Orleans, LA.
Baumeister et al. Novel small molecule ONC201 induces cell death in triple negative and non-triple negative breast cancer cells. 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference — Nov5 – Nov9; Boston, MA.
Stein et al. First-in-human dose escalation study of oral ONC201 in advanced solid tumors. 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference — Nov5 – Nov9; Boston, MA.
Allen et al. The small molecule TIC10 has potent anticancer efficacy mediated by induction of TRAIL production in normal and tumor cells.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Allen et al. ONC201 is non-toxic at efficacious doses in vitro and in vivo.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Kline et al. Early integrated stress response induction of ATF4 is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201/TIC10.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Kline et al. TRAIL pathway inducer ONC201/TIC10 primes multiple myeloma cells (MM) for apoptosis by downregulating X-linked inhibitor of apoptosis.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Prabhu et al. ONC201/TIC10 targets colorectal cancer stem cells and bulk tumor cells via an Akt-Foxo3a-TRAIL-dependent mechanism.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Talekar et al. ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin’s lymphoma.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Wagner et al. Cytotoxicity, Biochemical Activity, and Structural Analysis of ONC201 Clinical Material and Comparisons to a Biologically Inactive Isomer.
AACR 106th Annual Meeting 2015‐‐ Apr 18-22, 2015; Philadelphia, PA.
Imperato et al. Characterization of TIC10, a novel small molecule inducer of TRAIL, in combination with chemotherapy for lymphoma in vitro.
AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC.
Talekar et al. TRAIL-inducing agent -TIC10 and combinatorial therapeutics in pediatric lymphoma: a targeted approach.
AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC.
Prabhu et al. Therapeutic targeting of colorectal cancer stem cells by TRAIL-inducing small molecule TIC10.
AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC.
Allen et al. Kinase library siRNA screen identifies KSR1 as a synergistic therapeutic target in combination with TIC10.
AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC.
Allen et al. Potent anti-tumor effects of TIC10 require Foxo3a and TRAIL gene upregulation.
AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL.
Allen et al. The small molecule TIC10 has potent anticancer efficacy mediated by induction of TRAIL production in normal and tumor cells.
AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL.
Chi et al. Integrated Clinical Experience with ONC201 in H3 K27M Glioma 2018 ASCO June 1-5 Chicago IL
Arrillaga-Romany et al. Intratumoral Activity of ONC201 in Adult Recurrent Glioblastoma Patients 2018 ASCO June 1-5 Chicago IL
Stein et al. Safety and Pharmacodynamics of the DRD2 Antagonist ONC201 in Advanced Solid Tumor Patients with Weekly Oral Administration 2018 ASCO June 1-5 Chicago IL
Rodriguez-Rodriguez et al. Clinical activity of the selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC) 2017 ASCO June 2-6 Chicago IL
Stein et al. Anticancer and immunostimulatory activity of the imipridone ONC201, a selective DRD2 antagonist, in advanced cancer patients 2017 ASCO June 2-6 Chicago IL
Olszanski et al. “A dose-escalation study of imipridone ONC201 administered every one (QW) or three weeks (Q3W) in advanced solid tumors and multiple myeloma 2017 ASCO June 2-6 Chicago IL
Stein et al. First-in-human trial of ONC201 in patients with refractory solid tumors. 2016 ASCO – June 3 – June 7; Chicago, IL.
Lee et al. First-in-class small molecule ONC201 in b-cell malignancies. 2016 ASCO – June 3 – June 7; Chicago, IL.
Wagner, El-Deiry et al. Dose-intensified ONC201 to exert anti-metastatic efficacy and to promote intra-tumoral recruitment of NK-cells in mice. 2016 ASCO – June 3 – June 7; Chicago, IL.
Stein et al. First-in-human dose escalation study of oral ONC201 in advanced solid tumors. 2015 ASCO Annual Meeting — May29 – June2, 2015; Chicago, IL.
Zhao et al. ONC201, a small molecule Foxo3a activator, activity against patient-derived glioblastoma tumor-initiating cells.
J Clin Oncol 32, 2014 (suppl; abstr e13022).
Talekar et al. ONC201(TIC10) Induces TRAIL and Cell Death In Preclinical Models Of Pediatric Lymphoma.
November 15, 2013; Blood: 122 (21).
Ge et al. Venetoclax Synergistically Enhances the Antileukemic Activity of Imipridone ONC213, a Novel Imipridone ONC201 Analog, in Acute Myeloid Leukemia. 2018 ASH Dec. 1-4 San Diego, CA.
Romaguera et al. Integrated Stress Response and Immune Cell Infiltration in an Ibrutinib-refractory Mantle Cell Lymphoma Patient Following ONC201 Treatment.
Blood, 130(Suppl 1), 5163.
Prabhu et al. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies in vitro and in vivo through apoptosis via the integrated stress response pathway.
2017 ASH Dec. 9-12 Atlanta, GA.
Su et al. ONC213, A Novel Second Generation Analog of ONC201, Shows Promising Anti-leukemic Activity Against AML Cells in vitro and in vivo.
2017 ASH Dec. 9-12 Atlanta, GA.
Nii et al. The novel imipridone ONC212 induces pronounced anti-leukemia effects in vitro and in vivo and is highly synergistic with the BCL-2 inhibitor ABT-199.
2017 ASH Dec. 9-12 Atlanta, GA.
Prabhu et al. Single Agent and Combinatorial Efficacy of First-in-Class Small Molecule ONC201 in Acute Leukemia and Multiple Myeloma 2016 ASH Dec. 2 – Dec. 5 San Diego, CA
Tu et al. ONC201 Overcomes Chemotherapy Resistance By Upregulation of Bim in Multiple Myeloma 2016 ASH Dec. 2 – Dec. 5 San Diego, CA
Borthakur et al. A Phase I/II Clinical Trial of the First-in-Class GPCR Antagonist ONC201 in Relapsed/Refractory Acute Leukemias 2016 ASH Dec. 2 – Dec. 5 San Diego, CA
Nii et al. ONC212 Is a Potent Member of the Imipridone Class of Anti-Cancer Compounds That Induces p53-Independent Apoptosis in Hematological Malignancies 2016 ASH Dec. 2 – Dec. 5 San Diego, CA
Ishizawa et al. ONC201 Induces p53-Independent Apoptosis and Abrogates Stem Cell Function in Hematological Malignancies By Induction of ATF4 through Integrated Stress Response. 2015 ASH — Dec5 – Dec 8; Orlando, FL.
Duvic et al. ONC201 Induces Apoptosis in Cutaneous T-Cell Lymphoma Cells through a Mechanism That Involves the Integrated Stress Response and Inactivation of Jak/Stat Signaling. 2015 ASH — Dec5 – Dec 8; Orlando, FL.
Allen et al. ONC201 Exhibits Mutation-Independent Efficacy with Superior Potency in Non-Hodgkin Lymphoma and Multiple Myeloma. 2015 ASH — Dec5 – Dec 8; Orlando, FL.
Khan et al. ABT199 and ONC201 in Diffuse Large B Cell Lymphoma Cell Lines. 2015 ASH — Dec5 – Dec 8; Orlando, FL.
Ishizawa et al. ONC201 induces p53-independent apoptosis and cell cycle arrest in hematological malignancies and leukemic stem/progenitor cells by inducing ER stress and mTOR inhibition.
December 6, 2014; Blood: 124 (21).
Allen et al. ONC201 Possesses a Benign Safety Profile at Highly Efficacious Doses in Normal Human Cells and Animal Toxicology Studies
December 6, 2014; Blood: 124 (21).
Prabhu et al. ONC201 Depletes Cancer Stem Cells in Refractory Cancer Patient Samples Blood 2014 124:5219; published ahead of print
December 5, 2014.
Lulla et al. Caspase-dependent anti-tumor effects ONC201/TIC10 in Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM) Blood 2014 124:5224; published ahead of print December 5, 2014.
Prabhu et al. Small Molecule ONC201/TIC10 Induces Caspase-Dependent Apoptosis in Acute Lymphoblastic Leukemia Cells via Modulation of Bcl-2 and IAP Family Proteins Blood 2014 124:5237; published ahead of print December 5, 2014.
Wagner et al. Screen of small molecule ONC201/TIC10 identifies single agent activity and combinatorial efficacy with bortezomib, rituximab or dexamethasone in killing of acute lymphoblastic leukemia cells Blood 2014 124:5233; published ahead of print December 5, 2014.
Talekar et al. ONC201/TIC10 is Effective as a Monoagent and Synergizes with Chemotherapy to Induce Cell Death in Non-Hodgkin’s Lymphoma Blood 2014 124:5491; published ahead of print December 5, 2014.
Ishizawa et al. ONC201 Exerts p53-Independent Cytotoxicity Through TRAIL and DR5 Induction In Mantle Cell Lymphomas.
November 15, 2013; Blood: 122 (21).
ONC201 glioma clinical experience
Chi et al. Integrated clinical experience with ONC201 in previously-treated H3 K27M-mutant glioma patients. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi19,https://doi.org/10.1093/neuonc/noy148.067
Arrillaga-Romany et al. Tumor Tissue Penetration and Pharmacodynamics of ONC201 in Adult Recurrent Glioblastoma Patients. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi18–vi19,https://doi.org/10.1093/neuonc/noy148.066
Gardner et al. Phase I clinical trial of ONC201 in pediatric H3 K27M-mutant glioma or newly diagnosed DIPG. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi201, https://doi.org/10.1093/neuonc/noy148.836
DRD2 dysregulation in glioma and ONC201 preclinical efficacy
Prabhu et al. DRD5 is a modulator of glioma susceptibility to DRD2 antagonism by ONC201, Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi77–vi78,https://doi.org/10.1093/neuonc/noy148.317
Li et al. Molecular determinant of clinical response to ONC201, an inhibitor of dopamine receptor 2 (DRD2) signaling, in glioblastoma patients, Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi90, https://doi.org/10.1093/neuonc/noy148.375
Prabhu et al. ONC201: The first selective, non-competitive DRD2/3 antagonist for clinical neuro-oncology. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi71, https://doi.org/10.1093/neuonc/noy148.291
Tarapore et al. ONC201 in combination with radiation exhibits synergistic efficacy in high grade gliomas and other advanced cancers. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi72,https://doi.org/10.1093/neuonc/noy148.295
Utility of imipridone scaffold in neuro-oncology
Ishida et al. Imipridones Cause Metabolic Reprogramming and Elicit Unique Vulnerabilities in Glioblastoma. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi98–vi99, https://doi.org/10.1093/neuonc/noy148.411
Prabhu et al. Selective, non-competitive DRD2/3 antagonism by imipridone ONC206 is effective in tumors with dopamine receptor dysregulation. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi88, https://doi.org/10.1093/neuonc/noy148.366
Jung et al. ONC206, an imipridone family member, suppresses glioblastoma cells via blocking cancer stemness pathways. Neuro-Oncology, Volume 20, Issue suppl_6, 5 November 2018, Pages vi97, https://doi.org/10.1093/neuonc/noy148.406
Arrillaga-Romany et al. Clinical Evaluation of the Imipridone ONC201 in Recurrent Glioblastoma: Predictive and Pharmacodynamic Biomarker Analyses.
Neuro-Oncology, Volume 19. Issue suppl_6, 6 November 2017, Pages vi11–vi12, https://doi.org/10.1093/neuonc/nox168.042
Chi et al. K27M mutant gliomas are selectively killed by ONC201, a small molecule inhibitor of dopamine receptor D2.
Neuro-Oncology, Volume 19, Issue suppl_6, 6 November 2017, Pages vi81, https://doi.org/10.1093/neuonc/nox168.334
Madhukar et al. Differentiated pharmacology of the imipridone ONC201, the first selective DRD2/3 antagonist in clinical neuro-oncology.
Neuro-Oncology, Volume 19, Issue suppl_6, 6 November 2017, Pages vi81–vi82, https://doi.org/10.1093/neuonc/nox168.335
Prabhu et al. The small molecule imipridone ONC201 is active in glioblastoma with DRD2 pathway dysregulation.
Neuro-Oncology, Volume 19, Issue suppl_6, 6 November 2017, Pages vi60, https://doi.org/10.1093/neuonc/nox168.244
Jung et al. ONC206, an imipridone family member, suppresses glioma stem cell maintenance.
Neuro-Oncology, Volume 19, Issue suppl_6, 6 November 2017, Pages vi60, https://doi.org/10.1093/neuonc/nox168.242
Cuoco et al. Characterization of the novel anti-cancer therapeutic ONC201 and related analogs as non-competitive antagonists of the D2 dopamine receptor Experimental Biology 2018 Meeting
THE ROLE OF G PROTEIN-COUPLED RECEPTORS IN CANCER
Schalop and Allen GPCRs, Desirable Therapeutic Targets in Oncology
Drug Discovery and Development 2017 Jan.
Bar-Shavit et al. G-Protein Coupled Receptors in Cancer
International Journal of Molecular Sciences 2016, 17(8), 1320; doi:10.3390/ijms17081320
Liu et al. G protein coupled receptors as promising cancer targets.
Cancer Letters 2016 Jul 1;376(2):226-39
Insel et al. G Protein–Coupled Receptor (GPCR) Expression in Native Cells: “Novel” endoGPCRs as Physiologic Regulators and Therapeutic Targets.
Mol Pharmacol. 2015 Jul; 88(1): 181–187
O’Hayre et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer.
Nat Rev Cancer. 2013 Jun;13(6):412-24
Lappano et al. G protein-coupled receptors: novel targets for drug discovery in cancer.
Nat Rev Drug Discov. 2011 Jan;10(1):47-60
Gutkind et al. G-protein-coupled receptors and cancer.
Nat Rev Cancer. 2007 Feb;7(2):79-94.
Dirks et al. Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells. Cancer Cell. 2016 Jun 13;29(6):859-873. doi: 10.1016/j.ccell.2016.05.002.
Li et al. Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells. J Mol Cell Biol. 2017 Aug 1;9(4):302-314. doi: 10.1093/jmcb/mjx017.
Caragher SP, et al. Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma. Neuro Oncol. 2019 Jan 16. pii: 1589-18. doi: 10.1523/JNEUROSCI.1589-18.2018
Schalop et al. The Role of DRD2 in Cancer
Drug Discovery and Development 2016 Aug.
Caragher SP, et al. Monoamines in glioblastoma: complex biology with therapeutic potential Neuro Oncol. 2018 Jul 5;20(8):1014-1025. doi: 10.1093/neuonc/nox210
Studies indicating differentiated dopamine receptor expression in human cancers
| Tumor Type(s) | Conclusion | Reference |
| Small cell lung cancer | Elevated plasma dopamine & dopamine receptor expression in SCLC | Cherubini et al, 2016 |
| Glioblastoma | The DRD5 gene is downregulated in gliomas.
Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma DRD4 antagonists selectively inhibit patient-derived glioma stem cell proliferation and survival. DRD2 overexpression promotes glioma stem cell self-renewal. Blockade of DRD2 signaling inhibits tumorigenicity |
Huang et al. 2017 |
| Cervical cancer | DRD2 is associated with cervical cancer progression; cervical cancer cells respond to thioridazine | Mao et al, 2015 |
| Neuroendocrine tumors | DRD2 is expressed in 35% of GI neuroendocrine neoplasms | Diakatou et al, 2015 |
| Lung cancer | DRD2 is expressed in 74% of lung carcinoids | Kanakis et al, 2015 |
| Meningioma | DRD2 was expressed in 93% of meningiomas | Trott et al, 2015 |
| Pituitary adenoma | DRD2 is the highest expressed dopamine receptor in pituitary adenomas | Gabalec et al, 2015 |
| Pheochromocytoma | DRD2 mRNA & protein is expressed in pheochromocytomas | Saveanu et al, 2013 |
| Neuroendocrine tumors | 11/17 neuroendocrine tumors expressed DRD2 | Pawlikowski et al, 2011 |
| Pheochromocytoma/paraganglioma | DRD2 is highly expressed in pheochromocytomas and paragangliomas | Saveanu et al, 2011 |
| Neuroendocrine tumors | DRD2 was expressed in gastroenteropancreatic neuroendocrine tumors | Diakatou et al, 2011 |
| Cholangiocarcinoma | Elevated Dopamine secretion and DRD2 expression | Coufal M et al 2010 |
| Neuroendocrine tumors | DRD2 is expressed in the majority of low and intermediate grade neuroendocrine tumors | Srirajaskanthan et al, 2009 |
| Corticotroph adenomas | DRD2 is expressed in corticotroph adenomas | de Bruin et al, 2009 |
| Colon cancer | DRD2 genotypes can increase risk of colon cancer recurrence | Murphy et al, 2009 |
| Neuroendocrine tumors | DRD2 is expressed in neuroendocrine tumors, more prevalent in aggrestive tumors | Grossrubatscher et al, 2008 |
Studies indicating anti-tumor efficacy of DRD2 antagonists in preclinical models
| Tumor Type(s) | Conclusion | Reference(s) |
| Solid tumors | Trifluoperazine has anti-metastatic properties | Pulkoski-Gross et al, 2015 |
| Breast cancer | DRD2 agonists or antagonists kill MCF7 cells | Pornour et al, 2015 |
| Glioblastoma | Dopamine signaling: target in glioblastoma
Genetic knockdown or haloperidol has anticancer activity in GBM Dopamine receptor inhibition reduces cell motility and cross talks with Ras signaling |
Hodny et al,2014 |
| Breast cancer | Thioridazine and doxorubicin possess anticancer activity | K et al, 2014 |
| Neuroendocrine tumors | Inhibition of DRD2 and STTR2 has anticancer effects in midgut carcinoid cells | Zitzmann et al, 2013 |
| Neuroblastoma | Sertindole induces neuroblastoma cell death and autophagy | Shin et al, 2012 |
| Hepatocellular carcinoma | DRD2 inhibitors possess anticancer activity | Chen et al, 2011 |
| Neuroblastoma | Halopiredol possesses anticancer activity | Gasso et al, 2012 |
| Small cell lung cancer | Cortexolone possesses anticancer activity | Reina et al, 2011 |
| Glioblastoma | Eticlopride possess anticancer activity | Visnyei et al, 2011 |
| Prostate & NSCLC | Inhibition of DRD2 and STTR2 has anticancer effects | Arvigo et al, 2010 |
| Cholangiocarcinoma | DRD2 antagonism reduces dopamine-mediated tumor cell proliferation | Coufal M et al 2010 |
| Pancreatic cancer | DRD2 antagonism with pimozide and haloperidol induces ER stress and inhibits growth | Hoheisel et al 2016 |
| Glioblastoma | Thioridazine possesses anticancer activity | Cheng et al, 2015 |
| Cervical cancer | Mao et al, 2015 | |
| Murine breast cancer | Yin et al, 2015 | |
| Hepatocellular carcinoma | Lu et al, 2015 | |
| Ovarian cancer | Park et al, 2014; Rho et al, 2011; Byuen et al, 2012; | |
| Gastric cancer | Mu et al, 2014 | |
| Nasopharyngeal carcinoma | Lan et al, 2014 | |
| Breast cancer & leukemia | Sachlos et al, 2012 | |
| Cervical & endometrial cancer | Kang et al, 2012 | |
| Lymphoma | Spengler et al, 2011 | |
| Glioma and neuroblastoma | Gil-Ad et al, 2004 | |
| Lymphoma and leukemia | Zhelev et al, 2004 | |
| Breast cancer | Strobl et al, 1990 |