Publications

RESEARCH ARTICLES

Dopamine Receptor Antagonism

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

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.

Gliomas

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].

Hematological Malignancies
Cancer Stem Cells
ONC206, ONC212 and more

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

CONFERENCE ABSTRACTS

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.

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).

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).

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
DRD2 Expression in Human Cancers

Schalop et al. The Role of DRD2 in Cancer
Drug Discovery and Development 2016 Aug.

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
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