In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 5368-5368
Kurzfassung:
The perinucleolar compartment (PNC) is a nuclear body that forms specifically in highly malignant cancer cells. PNC prevalence is shown to reflect metastatic potential of cancer cells from solid tissue origins. A high-content screen was performed to identify small molecules that reduce PNC prevalence. Medicinal chemistry optimizations of confirmed hits yield metarrestin, having 95% of oral bioavailability and a PNC disassembly IC50 between 100 to 400 nM across multiple cancer cell lines. Metarrestin inhibits soft agar growth and the invasive capabilities of cancer cells in vitro. In vivo mouse xenograft metastatic studies showed that metarrestin effectively inhibits lung and/or liver metastasis of prostate cancer (PC3M), pancreatic cancer (organotypic spheroids of PANC1), and a breast cancer patient xenograft (PDX) model derived from metastatic cells isolated from a pleural effusion. Treated animals tolerate metarrestin well with no discernable impact on animal well-being including weight compared with control animals. These data supports the idea that the pharmacological disassembly of PNC produces the inhibition of malignant behavior of cancer cells both in vitro and in vivo. Cellular and molecular analyses of the mechanisms of action of metarrestin show that this compound induces significant and reversible changes in the nucleolar structure, accompanied by a selective reduction of pol I transcription. These studies suggest that PNC structural integrity directly associates with pol I function and nucleolar structure. Experiments are currently underway to identify the cellular factors and pathways by which metarrestin reduces PNCs, disrupts nucleolar structure, regulates transcriptions, and blocks malignant behaviors. Citation Format: Chen Wang, Kevin Frankowski, Teper Yaroslav, Samarjit Patnaik, Frank Schoenen, Noel Southall, Wei Sun, Steve Titus, Lesley Griner, Christopher Dextras, Jamey Sultan, Irawati Kandela, Marzena Lewandowska, Yi-Ping Wen, John Norton, Jin Sol Kang, Andrew Mazar, Wei Zhang, Jeffrey Aubé, Marc Ferrer, Udo Rudloff, Juan Jose Marugan, Sui Huang. Metarrestin effectively disassembles PNCs and inhibits metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5368. doi:10.1158/1538-7445.AM2015-5368
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-5368
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
Permalink
