1.Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition.
Henssen A1, Althoff K2, Odersky A3, Beckers A4, Koche R5, Speleman F4, Schäfers S2, Bell E6, Nortmeyer M6, Westermann F6, Preter K4, Florin A7, Heukamp L8, Spruessel A3, Astrahanseff K9, Lindner S3, Sadowski N3, Schramm A3, Astorgues-Xerri L10, Riveiro ME Clin Cancer Res. 2015 Dec 2. [Epub ahead of print]
PURPOSE: Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma.
2.Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies.
Odore E1,2, Lokiec F3, Cvitkovic E4,5, Bekradda M4, Herait P4,5, Bourdel F4, Kahatt C4, Raffoux E6, Stathis A7, Thieblemont C6, Quesnel B8, Cunningham D9, Riveiro ME4, Rezaï K3. Clin Pharmacokinet. 2016 Mar;55(3):397-405. doi: 10.1007/s40262-015-0327-6.
BACKGROUND AND OBJECTIVES: OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling.
3.BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells.
Coudé MM1,2, Braun T1,3, Berrou J1, Dupont M1, Bertrand S1, Masse A1, Raffoux E1,4, Itzykson R1,4, Delord M5, Riveiro ME6, Herait P7, Baruchel A1,8, Dombret H1,4, Gardin C1,3. Oncotarget. 2015 Jul 10;6(19):17698-712.
The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015.
4.BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer.
Asangani IA1, Wilder-Romans K2, Dommeti VL3, Krishnamurthy PM3, Apel IJ3, Escara-Wilke J3, Plymate SR4, Navone NM5, Wang S6, Feng FY7, Chinnaiyan AM8. Mol Cancer Res. 2016 Apr;14(4):324-31. doi: 10.1158/1541-7786.MCR-15-0472. Epub 2016 Jan 20.
Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively.
