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 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.

The Role of Surveillance versus Adjuvant Treatment in Stage I Germ Cell Tumors: Outcomes and Challenges

2015 ◽  
pp. e249-e252 ◽  
Author(s):  
Alan Horwich
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
Recurrence Risk ◽  
Good Prognosis ◽  
Rete Testis ◽  
Stage I ◽  
First Year ◽  
The Individual ◽  
Cure Rates ◽  
Risk Of Relapse

Germ cell cancers of the testis arise in young adults, and, if identified in stage I, have an excellent prognosis. Thus, we should minimize management-related toxicities. Surveillance (observation) following orchiectomy can avoid further treatment; however, patients who experience relapse receive more treatment than what would have been used during initial adjuvant therapy. For the individual patient, it is important to be aware of their particular risk of relapse, the treatment they would receive for the treatment of relapse and the alternative adjuvant approaches. For seminoma, the risk of relapse during surveillance is 15% to 20%; the size of the primary tumor and the presence of rete testis invasion are prognostic factors. Most relapses occur within 3 years; however, approximately 10% occur more than 5 years after orchiectomy. The alternative adjuvant strategies are either one cycle of carboplatin or radiotherapy (RT), which reduce recurrence risk to less than 5%. The cure rate is around 99%, regardless of which management option is implemented. For stage I nonseminoma, the risk of relapse during surveillance in unselected series is 26% to 30%. Lymphovascular invasion and the amount of embryonal carcinoma are risk factors. Most relapses occur within the first year after orchiectomy, and relapse after 3 years is rare. Ninety percent of relapse patterns are classified as “good prognosis,” and cure rates are 99%. The alternatives to surveillance include adjuvant strategies such as one cycle of adjuvant bleomycin/etoposide/cisplatin (BEP) chemotherapy; however, evidence is emerging that a single cycle is effective. There is controversy whether to offer surveillance for all patients or to offer adjuvant chemotherapy to select patients.

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

Individual Treatment with Stem Cell Rescue in Patients with Germ-Cell Tumors. Results of One Centrum.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5429-5429
Author(s):  
Jana Nepomucka ◽  
Jitka Abrahamova ◽  
Martin Foldyna ◽  
Zuzana Donatova ◽  
Drahomira Kordikova ◽  
...  
Keyword(s):  
Stem Cell ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
Salvage Treatment ◽  
Individual Treatment ◽  
High Dose ◽  
Line Treatment ◽  
Stem Cell Rescue ◽  
The Individual

Abstract Background: Treatment with high dose chemotherapy and autologous stem cell rescue in pacients with poor risk germ cell tumors is still controversial. Results of multicentric randomized EBMT study IT 94 presented at ASCO 2002 show benefit in 1-year EFS in high dose arm (52% versus 48%), 3-year EFS was the same in both arms (53%) in salvage treatment. Individual treatment with stem cell rescue as upfront treatment offers a survival benefit. Methods:Autologous stem cell rescue was provided in our center, from September 1997 to May 2006 to 52 patients. High dose chemotherapy was indicated to 32 patients in salvage setting after 2nd line of treatment (VeIP) and to 20 patients as upfront treatment after 1st line treatment (BEP). Median age was 29 years and tumor markers were elevated: HCG in 9 pts, AFP in 13 pts. Stem cell mobilization was performed after the 3rd cycle of VeIP or BEP in combination with G-CSF. The amount of CD34+ cell/kg b.w. was between 2,0 – 13.4×106. High - dose conditioning regimen CARBOPEC (carboplatin 1600 – 2 200 mg/m2, etoposide 1 800mg/m2, cyclophosphamide 6 400 mg/m2) was used. The treatment was well tolerated without transplant - related mortality. Results: WHO criteria non - hematological toxicity was predominantly grade 2 to 3. Engraftment was rapid, recovery of hematopoiesis in neutrofils over 1.0×109/l and platelets over 50×109/l was reached an average on days +10 and +13 respectively. Additional post-transplant treatment for persistence, progression or relaps had 20 patients (8pts had 2nd line treatment VEIP, 12pts had 3nd line treatment with paclitaxel+gemcitabine and 5 pts had retroperitoneal lymfadenectomy). The follow - up period ranges from 3 to 99 months, at present 38 (73 %) patients are alive, 14 (27 %) pts died. Median TTP of all pts is 10 months, median OS of all pts is 39 months. Median DFS of surviving pts is 38 months. Conclusion: high-dose chemotherapy with autologous stem cell rescue in patients with poor risk germ cell tumors is feasible and beneficial method of the individual treatment. High-dose chemotherapy as upfront treatment for poor prognosis germ cell tumors and as salvage treatment in good risk pts seems to be good possibility of the individual treatment.

Fertility problems in patients with germ cell tumors

2016 ◽  
Vol 21 (5) ◽  
pp. 275-280
Author(s):  
Elena V. Zhukovskaya
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
Reproductive Function ◽  
Anticancer Therapy ◽  
Sampling Procedure ◽  
Actual Problem ◽  
Age And Gender ◽  
And Gender ◽  
The Individual ◽  
Gender Features

This review highlights some of the aspects of the fertility in patients with germ cell tumors. This problem appears to be the very actual problem because of the possible impact not only anticancer therapy, but the tumor itself, coming from the human gonadal germ cells on the fertility. The individual histological types have been characterized by age and gender features. In patients with germ cell tumors, infertility is more common than in patients with other malignancies. Feasibility of the germ cell sampling procedure: the sperm and possibly, ovum, before the treatment in order to preserve the reproductive function of cured patients.

A Precious Diagnostic “Pearl”: The Necklace Pattern in Germ Cell Tumors of the Testis

2017 ◽  
Vol 26 (2) ◽  
pp. 148-150
Author(s):  
Justin Snow ◽  
Juan Miguel Mosquera ◽  
Theresa Scognamiglio ◽  
Brian D. Robinson ◽  
Francesca Khani
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumor ◽  
Germ Cell Tumors ◽  
Cell Tumor ◽  
Diagnostic Pitfall ◽  
Nonseminomatous Germ Cell Tumor ◽  
Hematoxylin And Eosin ◽  
The Individual ◽  
Hematoxylin And Eosin Stain ◽  
Nonseminomatous Germ Cell Tumors

Diffuse embryoma is a rare pattern of nonseminomatous germ cell tumor of the testis originally described in 1983. We report a case with this predominant pattern in an 18-year-old male with a painless palpable testicular mass. Although it is relatively common to see a diffuse embryoma pattern focally in mixed nonseminomatous germ cell tumors of the testis, it is rarely the predominant pattern and can represent a diagnostic pitfall on routine hematoxylin and eosin stain. We emphasize the importance of recognizing the individual components within the diffuse embryoma pattern, review the literature, and briefly discuss the ancillary immunohistochemical stains that may be utilized to help support the diagnosis.

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.

scholarly journals Germ cell tumor: A seven-year experience Children Welfare Teaching Hospital

2021 ◽  
Vol 63 (2) ◽  
pp. 60-64
Author(s):  
Raghad Majid Alsaeed ◽  
Afrah M. Jassim ◽  
Samaher A. Razaq ◽  
Mazin F. AL-Jadiry
Keyword(s):  
Overall Survival ◽  
Germ Cell ◽  
Germ Cell Tumor ◽  
Teaching Hospital ◽  
Germ Cell Tumors ◽  
Clinical Signs ◽  
Cell Tumor ◽  
Cure Rates ◽  
Record Review ◽  
Children Welfare

Background: Germ cell tumors are a rare heterogeneous group of cancers with high cure rates in the pediatric age group.Objectives: To study the clinical and pathological features in a group of patients with germ cell tumors and to evaluate their outcomes.Patients and methods: A record review was undertaken on a group of patients with germ cell tumor who were admitted to the Children Welfare Teaching Hospital in Baghdad during the years 2009 - 2015. Information on gender, age, clinical signs, pathological findings, treatment and overall survival rate were reviewed.Results: The patients had a mean age of 4.2 years (ranging from 1 month - 14 years). There were 45 girls and 16 boys. Abdominal pain was the most common presentation in 17 patients followed by a lower back mass in 16 patients. Primary sites included extra gonadal (sacrococcygeal 18, pelvis 5, vagina 4, gluteal 3, intra-cardiac, and one each for the mediastinum, orbit and rectum), and gonadal (18 ovarian and 9 testicular). After a mean period of follow-up of 42 months, the overall survival at 1 year was 59%.Conclusion: The prognosis of children with germ cell tumors is favorable, regardless the site and histopathology.

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