Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma

Moreno, Lucas; Barone, Giuseppe; DuBois, Steven G.; Molenaar, Jan J.; Fischer, Matthias; Schulte, Johannes H.; Eggert, Angelika; Schleiermacher, Gudrun; Speleman, Frank; Chesler, Louis; Geoerger, Birgit; Hogarty, Michael D.; Irwin, Meredith S.; Bird, Nick; Blanchard, Guy B.; Buckland, Sean; Caron, Hubert; Davis, Susan L.; Wilde, Bram De; Deubzer, Hedwig E.; Dolman, M. Emmy M.; Eilers, Martin; George, Rani E.; George, Sally L.; Štěrba, Jaroslav; Maris, John M.; Marshall, Lynley V.; Merchant, Melinda S.; Mortimer, Peter G.; Owens, Cormac; Philpott, Anna; Poon, Evon; Shay, Jerry W.; Tonelli, Roberto; Valteau‐Couanet, Dominique; Vassal, Gilles; Park, Julie R.; Pearson, Andrew D.J.

doi:10.1016/j.ejca.2020.05.010

Cited by 51 publications

(56 citation statements)

References 114 publications

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“…Multinational initiatives, such as the Innovative Therapies for Children with Cancer (ITCC) and the Neuroblastoma New Drug Development Strategy (NDDS), which focus on accelerating paediatric drug development, are essential in this process [20,21]. MDM2 and CDK4/6 inhibitors were amongst the targeted drugs selected by the NDDS [21,22]. To prevent further delay by (clinical) studies that are unlikely to be effective, it is pivotal to also publish negative findings.…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Schubert

Schild

Oirschot

et al. 2021

European Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Schubert

Schild

Oirschot

et al. 2021

European Journal of Cancer

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“…Thus, while the current therapy is effective in treating the favorable patients, it is not decisive for the unfavorable ones. Therefore, a new therapeutical approach for unfavorable patients is needed [14]. In this regard, a recent novel strategy for anticancer therapy using polyamines is under investigation [1,15].…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Spermine Metabolites Induce Apoptosis Associated with Increase of p53, caspase-3 and miR-34a in Both Neuroblastoma Cells, SJNKP and the N-Myc-Amplified Form IMR5

Kanamori

Finotti

Magno

et al. 2021

Cells

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Neuroblastoma (NB) is a common malignant solid tumor in children and accounts for 15% of childhood cancer mortality. Amplification of the N-Myc oncogene is a well-established poor prognostic marker in NB patients and strongly correlates with higher tumor aggression and resistance to treatment. New therapies for patients with N-Myc-amplified NB need to be developed. After treating NB cells with BSAO/SPM, the detection of apoptosis was determined after annexin V-FITC labeling and DNA staining with propidium iodide. The mitochondrial membrane potential activity was checked, labeling cells with the probe JC-1 dye. We analyzed, by real-time RT-PCR, the transcript of genes involved in the apoptotic process, to determine possible down- or upregulation of mRNAs after the treatment on SJNKP and the N-Myc-amplified IMR5 cell lines with BSAO/SPM. The experiments were carried out considering the proapoptotic genes Tp53 and caspase-3. After treatment with BSAO/SPM, both cell lines displayed increased mRNA levels for all these proapoptotic genes. Western blotting analysis with PARP and caspase-3 antibody support that BSAO/SPM treatment induces high levels of apoptosis in cells. The major conclusion is that BSAO/SPM treatment leads to antiproliferative and cytotoxic activity of both NB cell lines, associated with activation of apoptosis.

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“…Surprisingly, the second most selective drug for neuroblastoma was CX-5461, a compound that recently completed phase I clinical trial as a first-in-human selective inhibitor of RNA-POL I, but is not currently in clinical investigation in neuroblastoma 4 . The selective activity was striking (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the last decade, single-agent clinical trials in neuroblastoma have almost universally failed, even when the rationale for a new compound has been substantive 4 . For such an aggressive disease, identifying synergistic drug combinations is critical.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, the low mutation burden and resulting lack of neoantigens means immunotherapies have had an only modest impact 3 . Consequently, the overall survival in high-risk neuroblastoma has remained around 50% for the past 20 years 4 , meaning a promising small molecule inhibitor is of tremendous interest to treat this devastating disease.…”

Section: Introductionmentioning

confidence: 99%

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The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma

Pan

Wright

Chapple

et al. 2021

Preprint

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Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. These findings are important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity, often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

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Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma

Cited by 51 publications

References 114 publications

Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Enzymatic Spermine Metabolites Induce Apoptosis Associated with Increase of p53, caspase-3 and miR-34a in Both Neuroblastoma Cells, SJNKP and the N-Myc-Amplified Form IMR5

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma

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