The Role of Salvage High-Dose Chemotherapy in Relapsed Male Germ Cell Tumors

Oing, Christoph; Lorch, Anja

doi:10.1159/000489135

Cited by 18 publications

(17 citation statements)

References 36 publications

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“…In different experiences concerning adults with GCTs, use of HDCT in second or third relapse seems to give a worse prognosis. 15,21,22 Given the small size of our population, it is impossible to formulate a definitive judgment about the impact of HDCT on outcome.…”

Section: F I G U R E 2 Os Of Relapsed and Refractory Patientsmentioning

confidence: 99%

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience

Pasquale

D’Angelo²,

Crocoli

et al. 2019

Pediatric Blood & Cancer

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Background: Malignant germ cell tumors (GCTs) are a heterogeneous group of rare neoplasms in children. Optimal outcome is achieved with multimodal therapies for patients with both localized and advanced disease, especially after the introduction of platinum-based chemotherapy regimens. In this respect, data on salvage treatment for children with relapsed or platinum-refractory disease are still limited.Methods: Retrospective analysis of data regarding patients affected by malignant GCTs with platinum-refractory or relapsed disease after first-line treatment according to AIEOP TCGM 2004 protocol was conducted.Results: Twenty-one patients, 15 females and 6 males, were considered for the analysis. All 21 patients received second-line conventional chemotherapy (SLCT), two of these immediately after surgery for local relapse removal. Two patients showed a progression of disease during SLCT and died of disease shortly thereafter, whereas 19 patients were in partial remission (PR) or complete remission (CR) after SLCT. Treatment after SLCT consisted in surgery on residual tumor mass (9/19) followed by high dose of chemotherapy (HDCT) with autologous hematopoietic stem cell support (16/19). The overall survival (OS) and event-free survival of the whole populations are 71% and 66.6%, respectively. Platinum-refractory patients OS is 54.5% compared with 91.5% of the relapsed group. There were no treatment-related deaths. Conclusion:SLCT followed or not by HDCT is an effective salvage treatment for children with relapsed/refractory GCTs. However, the role of HDCT following SLCT needs to be further investigated, especially regarding the identification of specific patient subgroups, which can benefit from this more intensive treatment.

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Section: F I G U R E 2 Os Of Relapsed and Refractory Patientsmentioning

confidence: 99%

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience

Pasquale

D’Angelo²,

Crocoli

et al. 2019

Pediatric Blood & Cancer

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“…Despite high cure rates exceeding 90% over all stages, ~10–15% of patients with advanced disease relapse despite adequate multimodal first-line and first-salvage treatments and are deemed treatment refractory. 6 – 8 Such patients are usually incurable and face an awful prognosis with a life expectancy of a few months only. 6 – 8 …”

Section: Introductionmentioning

confidence: 99%

“… 6 – 8 Such patients are usually incurable and face an awful prognosis with a life expectancy of a few months only. 6 – 8 …”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms

et al. 2020

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Background Germ cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved, metastases, resistance to cisplatin-based therapy and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs. Methods Ten GCT cell lines, including cisplatin-resistant subclones and non-malignant controls, were treated with PaRi and screened for changes in viability (triphenyl tetrazolium chloride (XTT) assay), apoptosis rates (flow cytometry, caspase assay), the cell cycle (flow cytometry), the transcriptome (RNA-sequencing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and on protein level (western blot). Expression profiling was performed on paediatric and adult GCT tissues (expression microarrays, qRT-PCR, immunohistochemistry, ‘The Cancer Genome Atlas’ database). Results We demonstrate that adult GCTs highly express CDK4 , while paediatric GCTs strongly express CDK6 instead. Thus, both GCT types are potentially treatable by PaRi. GCTs presented as highly sensitive towards PaRi, which caused a decrease in viability, cell cycle arrest and apoptosis. Although GCTs mainly arrested in the G1/G0 phase, some embryonal carcinoma cell lines were able to bypass the G1/S checkpoint and progressed to the G2/M phase. We found that upregulation of CDK3 and downregulation of many mitosis regulation factors, like the HAUS genes, might be responsible for bypassing the G1/S checkpoint and termination of mitosis, respectively. We postulate that GCT cells do not tolerate these alterations in the cell cycle and eventually induce apoptosis. Conclusion Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs.

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“…In general, GCTs are treated by orchiectomy followed by chemo-or radiotherapy. Despite high cure rates exceeding 90% over all stages, about 20% of patients with advanced disease relapse and become treatment refractory [4][5][6]. Such patients are usually incurable and face a poor prognosis with a life expectancy of a few months only [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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

Kurz

Miklyaeva

Skowron

et al. 2020

Cancers

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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.

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The Role of Salvage High-Dose Chemotherapy in Relapsed Male Germ Cell Tumors

Cited by 18 publications

References 36 publications

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience

CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms

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

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