Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas.

Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal human astrocyte cells. TRX-E-009-1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, while also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009-1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumor effect was further enhanced with irradiation. Our findings indicate that TRX-E-009-1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.

High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer.

For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. SIGNIFICANCE: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.

In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer.

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.

Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

A Comparative Evaluation of Remineralizing Potential of Three Commercially Available Remineralizing Agents: An In Vitro Study.

AIM: An in vitro study to evaluate and compare the remineralization potential of commercially available remineralizing agents containing silver diamine fluoride (SDF), casein sucrose phosphate (CSP), casein phospho peptide-amorphous calcium phosphate (CPP-ACP) using DIAGNOdent. MATERIALS AND METHODS: Thirty freshly extracted premolars for orthodontic treatment were collected. Specimens were randomly divided into 3 groups of 10 each: group I: SDF, group II: CSP, group III: CPP-ACP. The samples were subjected to DIAGNOdent analysis for recording the baseline values. Specimens were placed in demineralizing solution incubated at 37°C for 72 hours. DIAGNOdent values were recorded after demineralization. Following this, remineralization procedure was carried out using 3 different remineralizing agents: group I samples with SDF, group II with CSP, and group III with CPP-ACP. The remineralization procedure was performed to group I once and repeated for 14 days for group II and group III and storage solution was changed every 24 hours. The samples were subjected to DIAGNOdent analysis after 72 hours, 7 days, and 14 days and values were recorded. RESULTS: The data were analysed using Statistical Package for the Social Sciences (SPSS) with analysis of variance (ANOVA) and post hoc test. Intragroup comparison of DIAGNOdent readings showed a highly significant difference between baseline, postdemineralization, and postremineralization values. Among intergroup comparison, SDF showed maximum remineralization values followed by CSP and CPP-ACP, respectively. CONCLUSION: Silver diamine fluoride, CSP, and CPP-ACP are proven to possess remineralization potential. CLINICAL SIGNIFICANCE: A comparative evaluation of these three remineralizing agents will aid in identifying most potent and effective agent in treating initial caries lesions in an effective noninvasive and child-friendly manner. HOW TO CITE THIS ARTICLE: Vinod D, Gopalakrishnan A, Subramani SM, et al. A Comparative Evaluation of Remineralizing Potential of Three Commercially Available Remineralizing Agents: An In Vitro Study. Int J Clin Pediatr Dent 2020;13(1):61-65.

Synthesis and anticancer activity of novel curcumin-quinolone hybrids.

A number of new curcumin-quinolone hybrids were synthesised from differently substituted 3-formyl-2-quinolones and vanillin and their in vitro cytotoxicity was determined on a panel of representative cell lines (A549, MCF7, SKOV3 and H460) using MTT assay. The most potent compound 14, was analysed for its mode of action using various cell biology experiments. SKOV3 cells treated with compound 14 showed distorted cell morphology under phase contrast imaging and induction of apoptosis was confirmed by Annexin V/PE assay. Further experiments on generation of reactive oxygen species (ROS) and cell cycle analysis revealed that these hybrids induce apoptosis by ROS generation and arrest cell cycle progression in S and G2/M phase.

Hematological and surgical management in Glanzmann's thrombasthenia: a case report.

Glanzmann's thrombasthenia (GT) is a rare, congenital, and moderate to severe platelet disorder. The bleeding time is increased, due to lack of platelet aggregation, since the patients with GT have deficient or dysfunctional integrin membrane glycoproteins IIb and IIIa essential for platelet aggregation. Children with GT are mostly diagnosed very early in life due to the spontaneous and unexplained mucocutaneous bleeding. It is quite a challenging task when any surgery is indicated for children with GT. This case report is about the medical and surgical management of an 11-year-old girl diagnosed with Glannzmann's thrombasthenia who had to undergo a maxillary cyst enucleation.