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Cell Death and Survival

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer

Avital Lev, Amriti R. Lulla, Brian C. Ross, Marie D. Ralff, Petr B. Makhov, David T. Dicker and Wafik S. El-Deiry
Avital Lev
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Amriti R. Lulla
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Brian C. Ross
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Marie D. Ralff
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Petr B. Makhov
Department of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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David T. Dicker
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Wafik S. El-Deiry
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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  • For correspondence: wafik.eldeiry@fccc.edu
DOI: 10.1158/1541-7786.MCR-17-0614
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Abstract

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel.

Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 1–13. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received October 20, 2017.
  • Revision received January 11, 2018.
  • Accepted January 23, 2018.
  • Published first March 27, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst March 27, 2018
doi: 10.1158/1541-7786.MCR-17-0614

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ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer
Avital Lev, Amriti R. Lulla, Brian C. Ross, Marie D. Ralff, Petr B. Makhov, David T. Dicker and Wafik S. El-Deiry
Mol Cancer Res March 27 2018 DOI: 10.1158/1541-7786.MCR-17-0614

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ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer
Avital Lev, Amriti R. Lulla, Brian C. Ross, Marie D. Ralff, Petr B. Makhov, David T. Dicker and Wafik S. El-Deiry
Mol Cancer Res March 27 2018 DOI: 10.1158/1541-7786.MCR-17-0614
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Molecular Cancer Research
eISSN: 1557-3125
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