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

by Selleckchem | Dec 15 2023

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.

Comments:

The study you described focuses on exploring alternative therapeutic options for Type II germ cell tumors (GCTs), which are the most common solid cancers in males aged 15 to 35 years. Traditional treatment methods involving cisplatin-based therapy have shown high cure rates but also lead to late toxicities. Given the young age of the patients affected by GCTs, these late toxicities significantly impact life expectancy. Additionally, the development of therapy resistance emphasizes the urgent need for new treatment strategies.

The study investigated epigenetic inhibitors as potential drugs for treating GCTs. Epigenetic modifiers play a crucial role in regulating gene expression and can be targeted to interfere with cancer cell growth. The researchers identified seven different epigenetic inhibitors that efficiently decreased cell viability in GCT cell lines, including cisplatin-resistant subclones. These inhibitors targeted various epigenetic modifiers and interactors, such as histone deacetylases, histone demethylases, histone methyltransferases, epigenetic readers, and polycomb-repressive complexes.

In addition to assessing cell viability, the researchers conducted in-depth analyses to understand the effects of these inhibitors on the histone modification landscape. They employed mass spectrometry-based techniques, revealing broader activity spectra than initially assumed for each drug. The study also investigated the impact of these drugs on the transcriptome of GCT cells through RNA sequencing. Common deregulations in gene expression of ion transporters and DNA-binding factors were observed. Furthermore, a kinase array analysis uncovered deregulations in signaling pathways like cAMP, JAK-STAT, and WNT.

In conclusion, the study identified seven epigenetic modifier drugs as potential candidates for treating cisplatin-resistant GCTs. The researchers not only demonstrated the efficacy of these drugs in decreasing cell viability but also extensively analyzed their off-target effects and modes of action. This comprehensive understanding is crucial for assessing the risks associated with these drugs and their suitability for individualized cancer treatment strategies.