Jostes, Sina Verena: The bromodomain inhibitor JQ1 as novel therapeutic option for type II testicular germ cell tumours [and] The role of SOX2 and SOX17 in regulating germ cell tumour pluripotency. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-55392
@phdthesis{handle:20.500.11811/8057,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-55392,
author = {{Sina Verena Jostes}},
title = {The bromodomain inhibitor JQ1 as novel therapeutic option for type II testicular germ cell tumours [and] The role of SOX2 and SOX17 in regulating germ cell tumour pluripotency},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = aug,

note = {The bromodomain inhibitor JQ1 as novel therapeutic option for type II testicular germ cell tumours
Type II testicular germ cell tumours (TGCTs) represent the most common malignancy in young men (19-35 years). They are classified as seminoma or embryonal carcinoma (EC; the stem cell population of non-seminomas). TGCTs are highly sensitive to radio- and chemotherapy, however 1-5% of TGCTs may develop resistance mechanisms to standard therapy regimens. Epigenetic drugs open a new avenue to cancer therapy and may present a promising alternative to treat recurrent TGCTs. JQ1 is an inhibitor of the BET family of bromodomain reader proteins. In TGCT cell lines, JQ1 treatment leads to upregulation of stress markers (i.e. CDKN1C, DDIT4, TSC22D1, TXNIP), induction of the differentiation marker HAND1, and downregulation of pluripotency-associated genes (i.e. LIN28, DPPA4, UTF1) [1]. This results in growth arrest and apoptosis in cisplatin-sensitive and cisplatin- resistant EC cells (at doses = 100 nM) and seminoma cells (at doses = 250 nM) [1, 2]. In line, EC xenografts in nude mice show reduced tumour burden when treated with JQ1 (50 mg / kg) compared to solvent controls. Additionally, JQ1-treated tumours showed reduced blood vessel count (lower CD31+), possibly due to JQ1- mediated downregulation of VEGFB. Altogether, this reflects the therapeutic potential of bromodomain inhibition for TGCTs. However, similar to TGCT cells, somatic control cells (here: Sertoli cells) responded with cell cycle arrest and apoptosis to JQ1 treatment. Thus, a more detailed analysis of possible side effects of JQ1 administration is recommended, before commissioning the drug for clinical use. Interestingly, JQ1 treatment had similar effects on TGCT cells as the HDAC inhibitor romidepsin (i.e. induction of stress markers GADD45A, GADD45B, RHOB, ID2) [1-3]. I now showed that JQ1 and romidepsin may elicit additive or synergistic effects on cytotoxicity levels of TGCT cells in vitro and in vivo. Since a combination of both drugs may, however, also increase potential side effects, the exact efficacy vs toxicity relationship of this treatment strategy needs further evaluation.},

url = {http://hdl.handle.net/20.500.11811/8057}
}

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