Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

Varun V. Prabhu, Mala K. Talekar, Amriti R. Lulla, C. Leah B. Kline, Lanlan Zhou, Junior Hall, A. Pieter J. Van den Heuvel, David T. Dicker, Jawad Babar, Stephan A. Grupp, Mathew J. Garnett, Ultan McDermott, Cyril H. Benes, Jeffrey J. Pu, David Claxton, Nadia Khan, Wolfgang Oster, Joshua E. Allen, Wafik S. El-Deiry

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

Original languageEnglish (US)
Pages (from-to)468-478
Number of pages11
JournalCell Cycle
Volume17
Issue number4
DOIs
StatePublished - Feb 16 2018

Fingerprint

Hematologic Neoplasms
Multiple Myeloma
Burkitt Lymphoma
Dexamethasone
Anaplastic Large-Cell Lymphoma
Mantle-Cell Lymphoma
Cytarabine
Heterografts
Acute Myeloid Leukemia
TIC10 compound
Azacitidine
Cutaneous T-Cell Lymphoma
Neoplasms
Cyclin D1
Sclerosis
Myeloid Cells
B-Cell Chronic Lymphocytic Leukemia
Standard of Care
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Caspases

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Prabhu, V. V., Talekar, M. K., Lulla, A. R., Kline, C. L. B., Zhou, L., Hall, J., ... El-Deiry, W. S. (2018). Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. Cell Cycle, 17(4), 468-478. https://doi.org/10.1080/15384101.2017.1403689
Prabhu, Varun V. ; Talekar, Mala K. ; Lulla, Amriti R. ; Kline, C. Leah B. ; Zhou, Lanlan ; Hall, Junior ; Van den Heuvel, A. Pieter J. ; Dicker, David T. ; Babar, Jawad ; Grupp, Stephan A. ; Garnett, Mathew J. ; McDermott, Ultan ; Benes, Cyril H. ; Pu, Jeffrey J. ; Claxton, David ; Khan, Nadia ; Oster, Wolfgang ; Allen, Joshua E. ; El-Deiry, Wafik S. / Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. In: Cell Cycle. 2018 ; Vol. 17, No. 4. pp. 468-478.
@article{4d056d3995ee4645bbad4aa1c8f44546,
title = "Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies",
abstract = "ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.",
author = "Prabhu, {Varun V.} and Talekar, {Mala K.} and Lulla, {Amriti R.} and Kline, {C. Leah B.} and Lanlan Zhou and Junior Hall and {Van den Heuvel}, {A. Pieter J.} and Dicker, {David T.} and Jawad Babar and Grupp, {Stephan A.} and Garnett, {Mathew J.} and Ultan McDermott and Benes, {Cyril H.} and Pu, {Jeffrey J.} and David Claxton and Nadia Khan and Wolfgang Oster and Allen, {Joshua E.} and El-Deiry, {Wafik S.}",
year = "2018",
month = "2",
day = "16",
doi = "10.1080/15384101.2017.1403689",
language = "English (US)",
volume = "17",
pages = "468--478",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "4",

}

Prabhu, VV, Talekar, MK, Lulla, AR, Kline, CLB, Zhou, L, Hall, J, Van den Heuvel, APJ, Dicker, DT, Babar, J, Grupp, SA, Garnett, MJ, McDermott, U, Benes, CH, Pu, JJ, Claxton, D, Khan, N, Oster, W, Allen, JE & El-Deiry, WS 2018, 'Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies', Cell Cycle, vol. 17, no. 4, pp. 468-478. https://doi.org/10.1080/15384101.2017.1403689

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. / Prabhu, Varun V.; Talekar, Mala K.; Lulla, Amriti R.; Kline, C. Leah B.; Zhou, Lanlan; Hall, Junior; Van den Heuvel, A. Pieter J.; Dicker, David T.; Babar, Jawad; Grupp, Stephan A.; Garnett, Mathew J.; McDermott, Ultan; Benes, Cyril H.; Pu, Jeffrey J.; Claxton, David; Khan, Nadia; Oster, Wolfgang; Allen, Joshua E.; El-Deiry, Wafik S.

In: Cell Cycle, Vol. 17, No. 4, 16.02.2018, p. 468-478.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

AU - Prabhu, Varun V.

AU - Talekar, Mala K.

AU - Lulla, Amriti R.

AU - Kline, C. Leah B.

AU - Zhou, Lanlan

AU - Hall, Junior

AU - Van den Heuvel, A. Pieter J.

AU - Dicker, David T.

AU - Babar, Jawad

AU - Grupp, Stephan A.

AU - Garnett, Mathew J.

AU - McDermott, Ultan

AU - Benes, Cyril H.

AU - Pu, Jeffrey J.

AU - Claxton, David

AU - Khan, Nadia

AU - Oster, Wolfgang

AU - Allen, Joshua E.

AU - El-Deiry, Wafik S.

PY - 2018/2/16

Y1 - 2018/2/16

N2 - ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

AB - ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

UR - http://www.scopus.com/inward/record.url?scp=85042221617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042221617&partnerID=8YFLogxK

U2 - 10.1080/15384101.2017.1403689

DO - 10.1080/15384101.2017.1403689

M3 - Article

VL - 17

SP - 468

EP - 478

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 4

ER -