New insights into signalling-pathway alterations in rhabdomyosarcoma

Zhu, Bo; Davie, Judith K.

doi:10.1038/bjc.2014.471

Cited by 39 publications

(35 citation statements)

References 35 publications

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“…Unfortunately, RMS patients that survive current cytotoxic drug therapies have an increased risk for several diseases later in life (3), emphasizing the critical need for development of new mechanism-based therapies which have fewer long term adverse effects. Results of PAX3-FOXO1A knockdown or overexpression studies in RMS and other cell lines demonstrate the functional importance of this fusion gene in maintaining the aggressive cancer cell phenotype and this is due, in part, to the pro-oncogenic PAX3-FOX01-regulated genes (39,42). Development of agents that target PAX3-FOXO1A is ongoing and includes thapsigargin, fenretinide, HDAC inhibitors, and polo-like kinase inhibitors; however, the efficacy of these compounds for clinical applications in ARMS chemotherapy is not known (43–47).…”

Section: Discussionmentioning

confidence: 99%

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

2017

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Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 is rhabdomyosarcomas which is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of β1-integrin which with PAX3-FOXO1A contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A.

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Section: Discussionmentioning

confidence: 99%

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

2017

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“…The majority of patients with metastatic RMS have alveolar histology, the molecular hallmark of which is paired box 3 (PAX3) or PAX7 gene fusion with forkhead box protein O1 (FOXO1). Unfortunately, efforts to target PAX‐FOXO1 fusion oncoproteins directly are not yet clinically viable . However, downstream pathways activated by PAX‐FOXO1 may be amenable to targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma

Malempati

Weigel

Yun

et al. 2018

Cancer

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Background The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children’s Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose‐intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin‐like growth factor‐1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone. Methods Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval‐compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites. Results One hundred sixty‐eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow‐up of 2.9 years, the 3‐year event‐free survival rate was 16% (95% confidence interval, 7%‐25%) with cixutumumab and 18% (95% confidence interval, 2%‐35%) with temozolomide. Conclusions The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.

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“…Present data confirmed that the HS mimic is able to counteract the pro-invasive effect of bFGF and the constitutive activation of FGFR4 and FGFR3. The implication of FGFR4 signaling in RMS tumorigenesis is well documented [54]. The receptor is, in fact, frequently overexpressed through gene amplification or direct transcription by the PAX3-FOXO1 fusion oncoprotein, the hallmark of alveolar RMS.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

Cassinelli

Favini

et al. 2016

Oncotarget

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The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.

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New insights into signalling-pathway alterations in rhabdomyosarcoma

Cited by 39 publications

References 35 publications

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

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