Publications

RESEARCH ARTICLES

First Imipridone ONC201 in Clinical Trials

Prabhu et al. ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia 2020 December doi: 10.1016/j.neo.2020.09.005

Arillaga-Romany et al. Biological activity of weekly ONC201 in adult recurrent glioblastoma patients. Neuro Oncology 2020 doi: 10.1093/neuonc/noz/164

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.

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.

 
H3 K27M-mutant Glioma and ONC201
Dopamine Receptor Antagonism

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

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.

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

He et al. Epidermal Growth Factor Receptor (EGFR) as a molecular determinant of glioblastoma response to dopamine receptor 2 (DRD2) inhibitors. Neuro-Oncology (2020). doi: https://doi.org/10.1093/neuonc/noaa188

Downstream Signaling Effect: Integrated Stress Response
Downstream Signaling Effect: TRAIL/DR5
Immune Effect

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.

Inhibition of Oxidative Phosphorylation and Mitochondrial Respiration (ClpP)

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

Gliomas

Pruss et al. Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxylglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma. British Journal of Cancer (2020) dot: 10.1038/s41416-020-0759-0

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

Other Solid Tumors

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.

Hematological Malignancies

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.

Cancer Stem Cells

CONFERENCE ABSTRACTS

2020
ONC201 Chemoprevention

14. TRAIL-Inducing Small Molecule ONC201 Prevents Intestinal Tumors in FAP Mouse Model.
June 22, 2020, 9:00AM

Combinatorial Activity:
1836. ONC201 Shows Synergistic Effect with the Androgen Receptor (AR) Inhibitor Darotulamide in Prostate Cancer Model.
June 22, 2020, 9:00AM

4808. ONC201 Decreases Protein Chaperone ClpX to Unleash Mitochondrial Protease ClpP Activity, Integrated Stress Response and Tumor Cell Death.
June 22, 2020, 9:00AM

3012. Novel Small Molecule ONC201 Induces Apoptosis in Gastric Adenocarcinoma and Exhibits Synergy with rhTRAIL.
June 22, 2020, 9:00AM

5407. Novel Imipridone Combination Therapies Targeting Oncohistone H3 K27M-Mutant Diffuse Midline Glioma (DMG).
June 22, 2020, 9:00AM

4042. Potent Synergistic Tumor Cell Suppression from Combination of ONC201 and Epigenetic Modulators EZH2 or HDAC Inhibitors Provides a Novel Treatment Strategy for Solid Tumors.
June 22, 2020, 9:00AM

3902. Novel Therapeutic Targeting of Epigenetic Aberrations in Pediatric Sarcomas through Combination of ONC201 and HDAC Inhibitors.
June 22, 2020, 9:00AM

5260. Preclinical Studies with ONC201 in Combination with Clinically Approved Chemotherapy as a Novel Treatment Strategy Against Small Cell Lung Cancer (SCLC).
June 22, 2020, 9:00AM

3904. The Novel Combination of PAC-1 and ONC201 Circumvent H3K27M-Driven Pro-Survival Gene Expression to Induce DIPG Cell Death.
June 22, 2020, 9:00AM

ONC201 Clinical Translation:
TBD Immuno-modulatory Activity of Selective DRD2 Antagonist ONC201, an Imipridone, in Metastatic Endometrial Cancer (mEC).
Date and time TBD

ONC201 Mechanism and Biomarkers:
3173. Predictive Biomarker Evaluation for the Anti-Cancer Imipridone ONC201.
June 22, 2020, 9:00AM.

4794. Mitochondrial Matrix Protease ClpP Agonists Inhibit Cell Growth and Cancer Stem Cell Function in Breast Cancer Cells.
June 22, 2020, 9:00AM

ONC206:
5688. IND-Enabling Characterization of ONC206 as the Next Bitopic DRD2 Antagonist for Neuro-oncology.
June 24, 2020, 9:00AM

5314. A Novel Dopamine Receptor D2 Antagonist (ONC206) Potentiates the Effects of Olaparib in Endometrial Cancer Cells through Inhibition of Cell Proliferation and Modulation of the mTOR Pathway.
June 22, 2020, 9:00AM

3797. Investigating the Anti-Cancer Effects of Novel Dopamine Receptor D2 Antagonists in a Panel of Human Cancer Cell Lines.
June 22, 2020, 9:00AM

5321. Novel Imipridone ONC206 Inhibits Cell Proliferation and Induces Apoptosis in Uterine Serous Cancer through Altering MAPK/AKT Signaling Network and Metabolic Reprogramming
June 22, 2020, 9:00AM

5336. Olaparib Potentiates the Anti-Proliferative and Anti-Metastatic Effects of ONC206 in Ovarian Cancer Cells.
June 22, 2020, 9:00AM

2958. ONC206, an Imipridone Derivative, Induces Cell Death through Activation of the Integrated Stress Response in Serous Endometrial Cancer In Vitro.
June 22, 2020, 9:00AM

ONC212:
6225. Addition of TRAIL Receptor Antagonists after Treatment with ONC201 or ONC212 Converts Pancreatic Cancer Cells from Anti-Proliferative to Apoptotic In Vitro.
June 22, 2020, 9:00AM

612. ONC212 Affects ClpXP Complex, Impairs Mitochondrial Bioenergetics and Synergizes with Glycolysis Inhibition in Pancreatic Cancer.
June 22, 2020, 9:00AM

2019
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

2018
2017

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

2016

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.

2015

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.

2013

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.

2012

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.

2011

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.

2020
2019

Arrillaga-Romany et al. Single agent ONC201 in adult recurrent H3 K27M-mutant glioma 2019 ASCO May 31-June 4 Chicago IL

Gardner et al. ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma 2019 ASCO May 31-June 4 Chicago IL

2018
2017
2016

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.

2015

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.

2014
2013

Talekar et al. ONC201(TIC10) Induces TRAIL and Cell Death In Preclinical Models Of Pediatric Lymphoma.
November 15, 2013; Blood: 122 (21).

2018
2017
2016
2015
2014

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.

2013

Ishizawa et al. ONC201 Exerts p53-Independent Cytotoxicity Through TRAIL and DR5 Induction In Mantle Cell Lymphomas.
November 15, 2013; Blood: 122 (21).

2020
2019

ONC201 H3 K27M-mutant glioma clinical experience

Arrillaga-Romany et al. Single agent ONC201 in previously-treated, progressive adult H3 K27M-mutant glioma Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Pages vi20–vi21,https://doi.org/10.1093/neuonc/noz175.077

Gardner et al. Phase I clinical trial of ONC201 in pediatric H3 K27M-mutant glioma or newly diagnosed DIPG

Kawakibi et al. Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi186,https://doi.org/10.1093/neuonc/noz175.773

ONC201: Receptor pharmacology and

Free et al. Receptor pharmacology of ONC201: The first bitopic DRD2 antagonist for clinical neuro-oncology Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi89,https://doi.org/10.1093/neuonc/noz175.365

Prabhu et al. Selective targeting of dopamine receptor dysregulation in high grade gliomas with ONC201

Sharma et al. Study of ONC201 in pre-clinical models of DIPG Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi192,https://doi.org/10.1093/neuonc/noz175.801

Zhou et al. Preclinical combination of ONC201 with radiotherapy or Temozolomide in GBM, DIPG and ATRT cell lines results in dopamine receptor antagonism, ATF4 induction and cell death Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi94,https://doi.org/10.1093/neuonc/noz175.388

Pruss et al. Metabolic rewiring by ONC201/TIC10 and 2-Deoxyglucose has synergistic anti-glioblastoma activity Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Pages vi40–vi41,https://doi.org/10.1093/neuonc/noz175.157

ONC201 glioma clinical experience

Prabhu et al. Imipridone Structure Activity Relationship Uncovers ONC206 as the Next Bitopic DRD2 Antagonist for Oncology with Differentiated Receptor Pharmacology Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi67,https://doi.org/10.1093/neuonc/noz175.271

Prabhu et al. IND-enabling Characterization of ONC206 as The Next Bitopic DRD2 antagonist for Neuro-oncology Neuro-Oncology,Volume 21, Issue Supplement_6, November 2019, Page vi97,https://doi.org/10.1093/neuonc/noz175.401

Malhotra et al. Role of ONC206 in regulating medulloblastoma tumor progression

2018

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

2017

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

THE ROLE OF G PROTEIN-COUPLED RECEPTORS IN CANCER

Overview Articles
The Dopamine Pathway in Cancers

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

Caragher et al. 2018

Dirks et al. 2016

Li 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
Anti-Cancer Effects of DRD2 Antagonism

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

Li et al, 2014

Lorimer et. al 2016

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