Magic™ Anti-Histone H3 (Phospho S28) monoclonal antibody, clone IUB39

Background Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive pediatric brain tumors that are characterized by a recurrent mutation (K27M) within the histone H3 encoding genes H3F3A and HIST1H3A/B/C. These mutations have been shown to induce a global reduction in the repressive histone modification H3K27me3, which together with widespread changes in DNA methylation patterns results in an extensive transcriptional reprogramming hampering the identification of single therapeutic targets based on a molecular rationale. Methods We applied a large-scale gene knockdown approach using a pooled short hairpin (sh)RNA library in combination with next-generation sequencing in order to identify DIPG-specific vulnerabilities. The therapeutic potential of specific inhibitors of candidate targets was validated in a secondary drug screen. Results We identified fibroblast growth factor receptor (FGFR) signaling and the serine/threonine protein phosphatase 2A (PP2A) as top depleted hits in patient-derived DIPG cell cultures and validated their lethal potential by FGF ligand depletion and genetic knockdown of the PP2A structural subunit PPP2R1A. Further, pharmacological inhibition of FGFR and PP2A signaling through ponatinib and LB-100 treatment, respectively, exhibited strong tumor-specific anti-proliferative and apoptotic activity in cultured DIPG cells. Conclusions Our findings suggest FGFR and PP2A signaling as potential new therapeutic targets for the treatment of DIPGs.

Oral squamous cell carcinoma (OSCC) has a dismal 50% five-year survival rate, emphasizing the need to develop reliable and sensitive tools for early diagnosis. In this study we evaluated the performance of 7 previously identified, potential mRNA biomarkers of OSCC in saliva samples of Hungarian patients. Expression of the putative OSCC biomarkers (DUSP1, OAZ1, H3F3A, IL1B, IL8, SAT and S100P), 2 biomarkers of inflammation (IL6 and TNF) and 8 putative normalizing genes was quantified from each sample using real-time quantitative PCR. In contrast with previous studies, the expression pattern of the 7 mRNA biomarkers was similar between OSCC patients and age-matched control patients in the Hungarian patient population. On the other hand, 5 of the 7 mRNA biomarkers were present at significantly higher levels in saliva samples of OSCC patients when compared to young control patients. The best biomarker combination could distinguish only the OSCC vs. young control patients, but not the OSCC vs. age-matched control patients. In conclusion, the significant differences between our results and previous studies, and the clinical characteristics of the patients suggest that inflammatory processes in the oral cavity may affect the performance of the 7 putative salivary mRNA biomarkers. Lastly, since IL6 mRNA was quantifiable in the majority of OSCC cases, but only in a few control samples, salivary IL6 mRNA may be utilized as part of a biomarker combination to detect OSCC.