Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

Paret, Claudia; Russo, Alexandra; Otto, Henrike; Mayer, Arnulf; Zahnreich, Sebastian; Wagner, Wolfgang; Samuel, David; Scharnhorst, David; Solomon, David A.; Dhall, Girish; Wong, Kenneth; Bender, Hannah; Alt, Francesca; Wingerter, Arthur; Neu, Marie A.; Beck, Olaf; Prawitt, Dirk; Eder, Stefan J.; Henninger, Nicole; Malki, Khalifa El; Lehmann, Nadine; Backes, Nora; Roth, Lea; Seidmann, Larissa; Sommer, Clemens; Brockmann, Marc A.; Staatz, Gundula; Schmidberger, Heinz; Faber, Jörg

doi:10.18632/oncotarget.23174

Cited by 26 publications

(33 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Martinez-Ricarte et al were able to classify 17 of 20 patients (including 2 children) with diffuse gliomas by analyzing only 7 genes in cell-free DNA from CSF [44]. Paret et al reported on one pediatric case of neuroepithelial high-grade tumor of the central nervous system showing a BCOR internal duplication, whose detection in plasma cell-free DNA correlated with relapse development [53]. The blood-brain barrier significantly restricts the amount of ctDNA entering the blood [7,22].…”

Section: Diagnostics and Therapeutic Stratificationmentioning

confidence: 99%

The pitfalls and promise of liquid biopsies for diagnosing and treating solid tumors in children: a review

et al. 2020

View full text Add to dashboard Cite

Cell-free DNA profiling using patient blood is emerging as a non-invasive complementary technique for cancer genomic characterization. Since these liquid biopsies will soon be integrated into clinical trial protocols for pediatric cancer treatment, clinicians should be informed about potential applications and advantages but also weaknesses and potential pitfalls. Small retrospective studies comparing genetic alterations detected in liquid biopsies with tumor biopsies for pediatric solid tumor types are encouraging. Molecular detection of tumor markers in cell-free DNA could be used for earlier therapy response monitoring and residual disease detection as well as enabling detection of pathognomonic and therapeutically relevant genomic alterations. Conclusion: Existing analyses of liquid biopsies from children with solid tumors increasingly suggest a potential relevance for molecular diagnostics, prognostic assessment, and therapeutic decision-making. Gaps remain in the types of tumors studied and value of detection methods applied. Here we review the current stand of liquid biopsy studies for pediatric solid tumors with a dedicated focus on cell-free DNA analysis. There is legitimate hope that integrating fully validated liquid biopsy-based innovations into the standard of care will advance patient monitoring and personalized treatment of children battling solid cancers. What is Known: • Liquid biopsies are finding their way into routine oncological screening, diagnosis, and disease monitoring in adult cancer types fast. • The most widely adopted source for liquid biopsies is blood although other easily accessible body fluids, such as saliva, pleural effusions, urine, or cerebrospinal fluid (CSF) can also serve as sources for liquid biopsies

show abstract

Section: Diagnostics and Therapeutic Stratificationmentioning

confidence: 99%

The pitfalls and promise of liquid biopsies for diagnosing and treating solid tumors in children: a review

et al. 2020

View full text Add to dashboard Cite

show abstract

“…This combination led to a sustained complete remission for 7.5 years and the patient is alive more than 10 years after initial diagnosis. Remission and survival are much longer than of most previously reported cases (Table S1) 1‐2,5‐11 . However, since this is a novel entity, the follow up for most of these cases is short.…”

Section: Discussionmentioning

confidence: 72%

A single supratentorial high‐grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival

Bremer

Kottke

Johann

et al. 2020

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Here, we present a patient with high-grade neuroepithelial tumors with mutations in the BCL6 corepressor BCOR (HGNET-BCOR), a rare, highly malignant brain tumor with poor prognosis. The patient underwent gross total tumor resection (GTR), high-dose chemotherapy, and, after local relapse, GTR, proton radiation, and chemotherapy. After a 7.5 year-long complete remission, the tumor recurred locally, was treated by GTR, and responded to temozolomide treatment. In addition to an internal tandem duplication in BCOR common to the majority of HGNET-BCOR cases, molecular analysis revealed a second BCOR mutation in this tumor: a frame shift mutation. The combination of these mutations was associated with relatively low BCOR expression compared to other HGNET-BCOR cases.

show abstract

“…Currently, the ATO agent is used in the promyelocytic leukemia therapy 11 , but its clinical potential over other types of tumors continue to be underexplored. It has a well-recognized effect in suppressing the SHH pathway by inhibiting GLI proteins, a pathway related to human cancer pathogenesis 7,12,13 .…”

Section: Discussionmentioning

confidence: 99%

Arsenic Trioxide exerts cytotoxic and radiosensitizing effects in pediatric Medulloblastoma cell lines of SHH Subgroup

Klinger

Delsin

Cruzeiro

et al. 2020

Sci Rep

View full text Add to dashboard Cite

We evaluated the potential effects of ATO in different pediatric SHH-MB cell lines (ONS-76: TP53wild type; DAOY and UW402: TP53-mutated). MB cell lines molecular subgroup was confirmed and TP53 mutations were validated. Cell viability, clonogenicity and apoptosis were evaluated after ATO treatment at different concentrations (1-16 µM) alone or combined with irradiation doses (0.5, 1, 2 and 4 Gy). Rad51 and Ku86 proteins were evaluated by WB. ATO treatment reduced cell viability for all SHH-MB cell lines. Significant decrease of clonogenic capacity and higher apoptosis rates were also observed after ATO exposure, being cell death more pronounced (>70%) for the SHH-MB TP53mutated. Combined treatment of ATO with irradiation also reduced colonies formation in UW402 tumor cells, which was independent of DNA damage repair proteins Rad51 and Ku86. In silico analyses suggested that a set of genes from cell cycle and p53 pathways are differentially expressed in SHH tumor subtypes, suggesting that cell lines may respond to therapies according to the gene expression profiles. Herein, we showed ATO cytotoxicity in pediatric SHH cell lines, with marked radiosensitizing effect for the MB-SHH TP53-mutated cells. These results highlight the potential of ATO, alone or in combination with radiotherapy, supporting further clinical investigations. Medulloblastoma (MB) is the most common malignant brain tumor in children, corresponding to approximately 20% of all brain tumors in patients less than 15 years of age. MB is responsible for significant morbidity and mortality rates 1. Recently, twelve distinct subgroups allocated to four main molecular classes (SHH, WNT, Group 3 and Group 4) have been recognized for MB: WNT-alpha and beta; SHH-alpha, beta, gamma and delta; Group 3-alpha, beta and gamma; and Group 4-alpha, beta, and gamma 2. Considering the clinical significance of the MB molecular classification, new therapies that contemplate the genetic aspects of the disease are required 3. The majority of SHH-MB cases presents somatic mutation in one or more genes of the Sonic Hedgehog (SHH) pathway (i.e., PTCH1, SUFU, or SMO), contributing to its constitutive activation. SHH signaling is essential for embryonic development, as well as it can lead to a tumor arising when aberrantly activated 4. The SHH-MB subgroup prognosis in children is mostly favorable, but the clinical outcome varies within this subgroup. SHH-MB alpha cases are rarely observed in infants and carry the poorest prognosis, which is associated with MYCN and GLI (glioma-associated oncogene homolog) amplification, and higher TP53 mutational burden. In contrast, SHH-MB beta and gamma subtypes affect mainly infants, being one-third of the SHH-MB beta cases metastatic at presentation with frequent focal PTEN deletions. The SHH-MB gamma is strongly related to MB with extensive nodularity (MBEN) histology, in general, presents wild type TP53, and excellent prognosis 2. Lastly,

show abstract

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

Cited by 26 publications

References 56 publications

The pitfalls and promise of liquid biopsies for diagnosing and treating solid tumors in children: a review

The pitfalls and promise of liquid biopsies for diagnosing and treating solid tumors in children: a review

A single supratentorial high‐grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival

Arsenic Trioxide exerts cytotoxic and radiosensitizing effects in pediatric Medulloblastoma cell lines of SHH Subgroup

Contact Info

Product

Resources

About