Rhabdomyosarcoma

Skapek, Stephen X.; Ferrari, Andrea; Gupta, Abha; Lupo, Philip J.; Butler, Erin; Shipley, Janet; Barr, Frederic G.; Hawkins, Douglas S.

doi:10.1038/s41572-018-0051-2

Cited by 722 publications

(724 citation statements)

References 225 publications

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“…Therefore, we focused on reducing chemotherapeutic dosage to decrease therapy-associated undesired effects. First, we used DBP to analyze the increase in priming after incubation with four standard of care RMS chemotherapeutic agents: the microtubule destabilizing agent vincristine, the alkylating molecule cyclophosphamide, the anthracycline antibiotic with antineoplastic activity doxorubicin and the topoisomerase inhibitor etoposide 24 . We performed DBP on three different RMS cell lines to account for the disease heterogeneity: two ARMS cell lines (CW9019 and RH4) and an ERMS cell line (RD).…”

Section: Novel Chemotherapy Combinations With Bh3 Mimetics To Increasmentioning

confidence: 99%

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Alcon

Manzano-Muñoz

Prada

et al. 2020

Preprint

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We use this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 prosurvival proteins, defeat resistance and avoid relapse to therapy. Indeed, we found that BH3 mimetics that selectively target BCL-xL and MCL-1 synergistically enhance the effect of the clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft (PDX) model and observed a reduction on tumor growth with a tendency to its stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. Finally, we identified the molecular mechanism by which RMS cells acquire resistance to vincristine: through the antiapoptotic protein MCL-1 for which we observed an enhanced binding between MCL-1 and BID after drug exposure, which is suppressed by the sequential addition of S63845. In conclusion, our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for BH3 mimetic combination with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency and decrease undesired secondary effects. Alcon et al.

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Section: Novel Chemotherapy Combinations With Bh3 Mimetics To Increasmentioning

confidence: 99%

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Alcon

Manzano-Muñoz

Prada

et al. 2020

Preprint

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“…Further improvement in survival is Abbreviations expected by the study of new drugs, possibly targeting RMS molecular alterations. 4,5 Alternatively, refinements of the current treatments could also improve results. 6 Optimization of the effective agents' doses and combinations could increase survival rate or maintain the same results but with less acute and late toxicity.…”

Section: Introductionmentioning

confidence: 99%

An unresolved issue in rhabdomyosarcoma treatment: The duration of chemotherapy

Bisogno

Hawkins

2020

Pediatric Blood & Cancer

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Clinical trials have tested different chemotherapy regimens to improve outcome for patients with rhabdomyosarcoma (RMS), but therapy duration has never been explicitly evaluated. North American trials evolved from longer (104 weeks) to shorter duration (24‐42 weeks). In Europe, treatment duration similarly evolved from 35 to 48 to 22 weeks for lower risk patients and from 56 to 72 to 27 weeks for higher risk patients. There was no evidence that chemotherapy duration influenced outcome over time. The recent RMS2005 trial showed an improved survival with the addition of 24 weeks of low‐dose chemotherapy. Treatment duration remains a question to be addressed in future trials.

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“…No single genetic lesion is linked to ERMS but chromosome gains (chr 2,8, 12 and 13) and loss of heterozygosity at 11p15.5 are characteristically seen (4). A few recurrent mutations occur in ERMS that include mutations in p53 (TP53), amplification of CDK4, upregulation of MYCN, and point mutations in RAS leading to its activation (1,(4)(5)(6). Recent studies have investigated whether improper epigenetic imprinting underlies the myogenic differentiation defect in RMS (7).…”

Section: Introductionmentioning

confidence: 99%

Deregulation of the histone H3K9 di-methylation landscape suppresses canonical Wnt signaling in embryonal rhabdomyosarcoma

Taneja

Pal

Leung

et al. 2020

Preprint

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The Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the H3K9 lysine methyltransferase G9a suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of G9a expression or activity reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in vivo. Mechanistically, G9a impacted Sp1 and p300 enrichment at the DKK1 promoter in a methylation-dependent manner. The reduced tumor growth upon G9a deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability.Together, our study demonstrates that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1-b-catenin node holds promise for differentiation therapy. receptor from the Frizzled (Fzd) family. The co-receptors LRP5/6 facilitate Wnt signaling. Activation of Wnt signaling leads to disruption of the destruction complex [APC, Axin, GSK3b and CK1a] which phosphorylates and degrades b-catenin. Induction of Wnt signaling results in accumulation of nonphosphorylated b-catenin (active b-catenin). b-catenin then translocates to the nucleus where it activates genes in cooperation with TCF/LEF1, but also other transcription factors (15). Neither of the two non-canonical pathways [Planar Cell Polarity pathway (PCP) and the Wnt/calcium signaling pathway] involve b-catenin. DKK1, a secreted protein interacts with LRP5/6 and antagonizes Wnt signaling by preventing LRP5/6 association with Wnt/Fzd complex (16). Despite the relevance of Wnt signaling in ERMS, epigenetic mechanisms leading to its suppression have not been described and could pave the way to development of targeted therapies.G9a, a lysine methyltransferase mediates mono and di-methylation of H3K9 (H3K9me1/2), which is primarily involved in transcriptional repression (17). Recent studies however have shown that G9a can also function as an activator in methylation-independent and dependent ways (18,19). G9a has been proposed to have oncogenic functions and its overexpression in leukaemia, gastric, lung, prostate cancer and alveolar rhabdomyosarcoma causes silencing of tumor suppressor genes through its H3K9me2 activity (18)(19)(20). In this study, we found that canonical Wnt/b-catenin signaling is epigenetically suppressed in ERMS. G9a activates expression of DKK1 in a methylation-dependent manner through an impact on Sp1 and p300 recruitment. Our data indicate the potential of targeting the G9a-DKK1 axis to activate Wnt signaling for the development of novel ERMS therapeutics. Conception and design: A Pal, R Taneja Development of methodology: A Pal, JY Leung, G Ang, VK Rao, HJ Lim, L Pignata Acquisition of...

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Rhabdomyosarcoma

Cited by 722 publications

References 225 publications

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

An unresolved issue in rhabdomyosarcoma treatment: The duration of chemotherapy

Deregulation of the histone H3K9 di-methylation landscape suppresses canonical Wnt signaling in embryonal rhabdomyosarcoma

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