Abstract 118: Targeting cancer with a novel BET bromodomain inhibitor ODM-207

Autor: Reetta Riikonen, Tarja Ikonen, Pekka Kallio, Juha Rantala, Aravind A B, Susanta Samajdar, Mari Björkman, Murali Ramachandra, Elina Mattila, Girish Daginakatte, Mahaboobi Jaleel, Anu-Maarit Moilanen, Chandrasekhar Abbineni, Sivapriya Marappan
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:118-118
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2017-118
Popis: Background: Bromodomain and extra-terminal (BET) family proteins are dual bromodomain-containing epigenetic readers that bind to acetylated-lysine residues at gene promoter and enhancer elements in histones and recruit protein complexes to promote transcriptional elongation. Recent evidence demonstrates that BET bromodomain inhibition leads to anti-proliferative activity in pre-clinical models of many hematological malignancies and solid tumors. Selective inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for the treatment of cancer. In this study, we evaluated the antitumor activity of ODM-207, a novel, potent and highly selective BET bromodomain inhibitor. Methods and Results: ODM-207 is a potent and selective BET inhibitor that is structurally unrelated to the benzodiazepine like inhibitors such as JQ1, I-BET762, and OTX015. We tested the preclinical activity of ODM-207 across multiple tumor types in a 4-day growth inhibition in vitro assay. ODM-207 potently inhibits cell viability of a wide range of hematological and solid tumor cell lines. ODM-207 also shows potent antiproliferative effects in patient-derived cancer cells representing various tumor types. In VCaP prostate cancer cell lines, ODM-207 induced apoptosis consistent with increased expression of pro-apoptotic regulators, whereas potent antiproliferative effects associated with cell cycle arrest and cellular senescence were seen in e.g. LNCaP prostate cancer cell line. To gain insight on mechanisms of acquired BET inhibitor resistance, we generated a cell line with resistance to BET-inhibition by culturing LNCaP prostate cancer cells with increasing concentrations of OTX015, a potent and selective BET-inhibitor. Interestingly, ODM-207 is also able to inhibit proliferation and downregulate Myc levels in cells that have acquired resistance to BET-inhibitors OTX015 and I-BET762. In xenograft models, oral treatment with ODM-207 significantly inhibits tumor growth at a dose which is well tolerated. Conclusions: In summary, these studies demonstrate that ODM-207 is a potent inhibitor of BET proteins in models of hematologic malignancies and solid tumors in vitro and in vivo and support its clinical development for the treatment of cancer. Citation Format: Anu-Maarit Moilanen, Mari Björkman, Reetta Riikonen, Chandrasekhar Abbineni, Mahaboobi Jaleel, Sivapriya Marappan, Tarja Ikonen, Girish Daginakatte, Aravind A B, Elina Mattila, Juha Rantala, Susanta Samajdar, Murali Ramachandra, Pekka Kallio. Targeting cancer with a novel BET bromodomain inhibitor ODM-207 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 118. doi:10.1158/1538-7445.AM2017-118
Databáze: OpenAIRE