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ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer
Mol Cancer Res. 2018 Mar 27;16(5) :754-766
PMID: 29588330    PMCID: PMC5932216    URL: https://www.ncbi.nlm.nih.gov/pubmed/29588330
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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. (c)2018 AACR.
Notes
1557-3125 Lev, Avital Lulla, Amriti R Ross, Brian C Ralff, Marie D Makhov, Petr B Dicker, David T El-Deiry, Wafik S R01 CA173453/CA/NCI NIH HHS/United States Journal Article United States Mol Cancer Res. 2018 Mar 27. pii: 1541-7786.MCR-17-0614. doi: 10.1158/1541-7786.MCR-17-0614. R01 CA173453/CA/NCI NIH HHS/