Publications
RESEARCH ARTICLES
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
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 May 12
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 New Big-Data Paradigm for Target Identification and Drug Discovery doi: https://doi.org/10.1101/134973
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
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.
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 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).
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).
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
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.
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 | 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 |
|
| 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 |
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