scholarly journals ARID1A Regulates Transcription and the Epigenetic Landscape via POLE and DMAP1 While ARID1A Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 905 ◽  
Author(s):  
Lukas Kurz ◽  
Alissa Miklyaeva ◽  
Margaretha A. Skowron ◽  
Nina Overbeck ◽  
Gereon Poschmann ◽  
...  
Keyword(s):  
Germ Cell ◽  
Dna Methyltransferase ◽  
Synthetic Lethality ◽  
Germ Cell Tumors ◽  
Epigenetic Landscape ◽  
Loss Of Function ◽  
Pharmacological Inhibition ◽  
Promising Target ◽  
Cure Rates ◽  
Tumor Types

Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs.

scholarly journals Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Melanie R. Müller ◽  
Aaron Burmeister ◽  
Margaretha A. Skowron ◽  
Alexa Stephan ◽  
Felix Bremmer ◽  
...  
Keyword(s):  
Germ Cell ◽  
Histone Deacetylases ◽  
Germ Cell Tumors ◽  
Therapy Resistance ◽  
Epigenetic Landscape ◽  
Drug Study ◽  
Epigenetic Modifiers ◽  
Dna Binding Factors ◽  
The Individual ◽  
Cure Rates

Abstract Background Type II germ cell tumors (GCT) are the most common solid cancers in males of age 15 to 35 years. Treatment of these tumors includes cisplatin-based therapy achieving high cure rates, but also leading to late toxicities. As mainly young men are suffering from GCTs, late toxicities play a major role regarding life expectancy, and the development of therapy resistance emphasizes the need for alternative therapeutic options. GCTs are highly susceptible to interference with the epigenetic landscape; therefore, this study focuses on screening of drugs against epigenetic factors as a treatment option for GCTs. Results We present seven different epigenetic inhibitors efficiently decreasing cell viability in GCT cell lines including cisplatin-resistant subclones at low concentrations by targeting epigenetic modifiers and interactors, like histone deacetylases (Quisinostat), histone demethylases (JIB-04), histone methyltransferases (Chaetocin), epigenetic readers (MZ-1, LP99) and polycomb-repressive complexes (PRT4165, GSK343). Mass spectrometry-based analyses of the histone modification landscape revealed effects beyond the expected mode-of-action of each drug, suggesting a wider spectrum of activity than initially assumed. Moreover, we characterized the effects of each drug on the transcriptome of GCT cells by RNA sequencing and found common deregulations in gene expression of ion transporters and DNA-binding factors. A kinase array revealed deregulations of signaling pathways, like cAMP, JAK-STAT and WNT. Conclusion Our study identified seven drugs against epigenetic modifiers to treat cisplatin-resistant GCTs. Further, we extensively analyzed off-target effects and modes-of-action, which are important for risk assessment of the individual drugs.

scholarly journals State-of-the-Art Management of Germ Cell Tumors

2018 ◽  
pp. 319-323 ◽  
Author(s):  
Darren R. Feldman
Keyword(s):  
Germ Cell ◽  
State Of The Art ◽  
Early Stage ◽  
Germ Cell Tumors ◽  
High Stakes ◽  
Inappropriate Use ◽  
Common Mistake ◽  
Relative Rarity ◽  
Cure Rates ◽  
Perfect Storm

The state of the art management of germ cell tumors (GCT) in 2018 does not include novel agents targeting genomic alterations or exciting immunologic-based approaches but rather the avoidance of pitfalls in everyday practice. The relative rarity of GCT and high curability with correct management create the "perfect storm" for high-stakes errors to occur. This review focuses on several common pitfalls that should be avoided in staging and management of early-stage and advanced GCT in order to maximize patient outcomes. A particularly frequent misstep is to base treatment decisions on pre- rather than postorchiectomy tumor markers that, depending on marker directionality, can lead to either undertreatment with potentially inferior outcomes or overtreatment with excess toxicity. Another common mistake is the failure to consider the unique ability of GCT to differentiate and the distinct biology of teratoma (chemoresistance and lack of increased glucose uptake compared with normal tissue), which exerts a pervasive influence on nonseminoma management. This may lead to inappropriate use of PET scan to evaluate the postchemotherapy residual mass and, if negative, the conclusion that surgery is not needed whereas (FDG-negative) teratoma should be removed. It could also result in administration of additional unnecessary chemotherapy to patients with marker normalization but without robust radiographic response after 3 to 4 cycles of BEP. Finally, oncologists should strive to maintain standard chemotherapy doses, not substitute carboplatin for cisplatin, and refer to expert centers when expertise (e.g., RPLND) is not available locally in order to achieve optimal cure rates in advanced disease.

scholarly journals GERM-01. GENETIC AND EPIGENETIC LANDSCAPE OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv21-iv22
Author(s):  
Koichi Ichimura ◽  
Yoshiko Nakano ◽  
Kai Yamasaki ◽  
Mai Kitahara ◽  
Kaishi Satomi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Epigenetic Landscape

scholarly journals CBMS-11 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii4-ii5
Author(s):  
Arata Tomiyama ◽  
Eita Uchida ◽  
Daisuke Kawauchi ◽  
Kojiro Wada ◽  
Kouchi Ichimura
Keyword(s):  
Germ Cell ◽  
Cell Line ◽  
Therapeutic Target ◽  
Germ Cell Tumors ◽  
Tumor Cell Line ◽  
Loss Of Function ◽  
Novel Therapy ◽  
Intracranial Germ Cell Tumor ◽  
Protein Ubiquitination ◽  
Novel Therapeutic

Abstract Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.

scholarly journals Targeting Germ Cell Tumors with the Newly Synthesized Flavanone-Derived Compound MLo1302 Efficiently Reduces Tumor Cell Viability and Induces Apoptosis and Cell Cycle Arrest

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 73
Author(s):  
João Lobo ◽  
Ana Rita Cardoso ◽  
Vera Miranda-Gonçalves ◽  
Leendert H. J. Looijenga ◽  
Marie Lopez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Cell Viability ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Dna Methyltransferase ◽  
Germ Cell Tumors ◽  
Flavonoid Compound ◽  
Testicular Germ Cell ◽  
Cycle Arrest

Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients.

scholarly journals High DNA Methyltransferase 3B Expression Mediates 5-Aza-Deoxycytidine Hypersensitivity in Testicular Germ Cell Tumors

2009 ◽  
Vol 69 (24) ◽  
pp. 9360-9366 ◽  
Author(s):  
Maroun J. Beyrouthy ◽  
Kristen M. Garner ◽  
Mary P. Hever ◽  
Sarah J. Freemantle ◽  
Alan Eastman ◽  
...  
Keyword(s):  
Germ Cell ◽  
Dna Methyltransferase ◽  
Germ Cell Tumors ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Dna Methyltransferase 3B

scholarly journals SPDR-06 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii7-ii7
Author(s):  
Arata Tomiyama ◽  
Eita Uchida ◽  
Tatsuya Kobayashi ◽  
Kojiro Wada ◽  
Kouichi Ichimura
Keyword(s):  
Germ Cell ◽  
Cell Line ◽  
Therapeutic Target ◽  
Germ Cell Tumors ◽  
Tumor Cell Line ◽  
Loss Of Function ◽  
Novel Therapy ◽  
Intracranial Germ Cell Tumor ◽  
Protein Ubiquitination ◽  
Novel Therapeutic

Abstract Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.

scholarly journals GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT NON-GERMINOMATOUS CNS GERM CELL TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii332-iii332
Author(s):  
Arata Tomiyama ◽  
Eita Uchida ◽  
Kojiro Wada ◽  
Koichi Ichimura
Keyword(s):  
Germ Cell ◽  
Cell Line ◽  
Therapeutic Target ◽  
Germ Cell Tumors ◽  
Tumor Cell Line ◽  
Loss Of Function ◽  
Novel Therapy ◽  
Intracranial Germ Cell Tumor ◽  
Protein Ubiquitination ◽  
Novel Therapeutic

Abstract Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.

Management of Ovarian Germ Cell Tumors

2007 ◽  
Vol 25 (20) ◽  
pp. 2938-2943 ◽  
Author(s):  
David M. Gershenson
Keyword(s):  
Prognostic Factors ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Reproductive Function ◽  
Advanced Stage ◽  
Early Stage Disease ◽  
Fertility Sparing Surgery ◽  
Stage Disease ◽  
Fertility Sparing ◽  
Cure Rates

Purpose To review contemporary management of malignant ovarian germ cell tumors (MOGCT). Design The literature on the topic of MOGCT is reviewed, including pathology, prognostic factors, surgical strategies, postoperative therapy, late effects of therapy, and treatment of recurrence. Results Prognostic factors for MOGCT include the International Federation of Gynecology and Obstetrics staging system's stage, residual disease, histologic type, and elevation of serum tumor markers. Fertility-sparing surgery is possible in a large proportion of patients. The importance of comprehensive surgical staging is somewhat controversial. For patients with advanced-stage disease, maximum cytoreductive surgery appears to be beneficial. Although second-look surgery is not recommended routinely, selected patients may benefit from secondary cytoreduction. For those patients who require postoperative chemotherapy, standard therapy consists of the combination of bleomycin, etoposide, and cisplatin. However, there is a growing trend toward surveillance; this strategy continues to be studied. Although premature menopause may occur in a small proportion of patients, at least 80% of those who undergo fertility-sparing surgery and chemotherapy may expect to preserve reproductive function. For patients with early-stage disease, cure rates approach 100%. For those with advanced-stage disease, cure rates are reportedly at least 75%. Conclusion MOGCT is a rare malignancy that principally affects girls and young women. With optimal therapy, the prognosis is excellent, and most patients may retain reproductive function.

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