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A foretaste for pediatric glioblastoma therapy: targeting the NF-kB pathway with DHMEQ
María Sol Brassesco1, Gabriela Molinari Roberto2, Lara Elis Delsin2
1Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, CEP 14040-901, Ribeirão Preto, SP, Brazil. solbrassesco@usp.br.
Purpose:
While pediatric glioblastomas are molecularly distinct from adult counterparts, the activation of NF-kB is partially shared by both subsets, playing key roles in tumor propagation and treatment response.
Results:
We show that, in vitro, dehydroxymethylepoxyquinomicin (DHMEQ) impairs growth and invasiveness. Xenograft response to the drug alone varied according to the model, being more effective in KNS42-derived tumors. In combination, SF188-derived tumors were more sensitive to temozolomide while KNS42-derived tumors responded better to the combination with radiotherapy, with continued tumor regression.
Conclusion:
Taken together, our results strengthen the potential usefulness of NF-kB inhibition in future therapeutic strategies to overcome this incurable disease.
Insights
NF-kB inhibition shows promise for treating pediatric glioblastomas, a brain tumor distinct from adult types. Dehydroxymethylepoxyquinomicin (DHMEQ) demonstrated effectiveness in preclinical models, suggesting new therapeutic avenues.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pediatric glioblastomas (pGBMs) are distinct from adult forms but share NF-kB pathway activation.
- NF-kB signaling is crucial for tumor growth and response to therapy in pGBMs.
Purpose of the Study:
- To investigate the therapeutic potential of NF-kB inhibition in pediatric glioblastoma.
- To evaluate the efficacy of dehydroxymethylepoxyquinomicin (DHMEQ) in preclinical models of pGBM.
Main Methods:
- In vitro studies assessing DHMEQ's impact on glioblastoma cell growth and invasiveness.
- In vivo xenograft models (KNS42 and SF188) to evaluate DHMEQ monotherapy and combination treatments.
Main Results:
- DHMEQ impaired glioblastoma cell growth and invasiveness in vitro.
- Xenograft responses varied: DHMEQ was more effective in KNS42 models. SF188 models showed increased sensitivity to temozolomide with DHMEQ. KNS42 models responded better to DHMEQ combined with radiotherapy, leading to sustained regression.
Conclusions:
- NF-kB inhibition, exemplified by DHMEQ, presents a viable strategy for pediatric glioblastoma treatment.
- Combination therapies involving NF-kB inhibitors may overcome treatment resistance in this aggressive brain tumor.
