Childhood Rhabdomyosarcoma: New Insight on Biology and Treatment

Huh, Winston W.; Skapek, Stephen X.

doi:10.1007/s11912-010-0130-3

Cited by 91 publications

(67 citation statements)

References 48 publications

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“…As both CHLA-20 and SK-N-BE (2) cell lines are derived from samples of patients who relapsed after chemotherapy, we use them to develop aggressive tumor models for rigorous screening of anticancer agents. All treatments commenced when the tumor sizes reached 0.25 cm 3 . In both neuroblastoma models, after 2 weeks of treatment, tumor growth delay was observed with evofosfamide or topotecan as monotherapies ( Fig.…”

Section: Improved Antiproliferation Effects Of Evofosfamide When Combmentioning

confidence: 99%

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Zhang

Marrano

et al. 2016

Clinical Cancer Research

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Purpose: Tumor cells residing in tumor hypoxic zones are a major cause of drug resistance and tumor relapse. In this study, we investigated the efficacy of evofosfamide, a hypoxia-activated prodrug, and its combination with topotecan in neuroblastoma and rhabdomyosarcoma preclinical models.Experimental Design: Neuroblastoma and rhabdomyosarcoma cells were tested in vitro to assess the effect of evofosfamide on cell proliferation, both as a single agent and in combination with topotecan. In vivo antitumor activity was evaluated in different xenograft models. Animal survival was studied with the neuroblastoma metastatic tumor model.Results: All tested cell lines showed response to evofosfamide under normoxic conditions, but when exposed to hypoxia overnight, a 2-to 65-fold decrease of IC 50 was observed. Adding topotecan to the evofosfamide treatment significantly increased cytotoxicity in vitro. In neuroblastoma xenograft models, single-agent evofosfamide treatment delayed tumor growth. Complete tumor regression was observed in the combined topotecan/evofosfamide treatment group after 2-week treatment. Combined treatment also improved survival in a neuroblastoma metastatic model, compared to singleagent treatments. In rhabdomyosarcoma xenograft models, combined treatment was more effective than single agents. We also showed that evofosfamide mostly targeted tumor cells within hypoxic regions while topotecan was more effective to tumor cells in normoxic regions. Combined treatment induced tumor cell apoptosis in both normoxic and hypoxic regions.Conclusions: Evofosfamide shows antitumor effects in neuroblastoma and rhabdomyosarcoma xenografts. Compared with single-agent, evofosfamide/topotecan, combined therapy improves tumor response, delays tumor relapse, and enhances animal survival in preclinical tumor models. Clin Cancer Res; 22(11); 2697-708. Ó2015 AACR.

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Section: Improved Antiproliferation Effects Of Evofosfamide When Combmentioning

confidence: 99%

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Zhang

Marrano

et al. 2016

Clinical Cancer Research

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“…Although significant progress has been made during the last decades in the treatment and prognosis of pediatric malignancies, high mortality is still prevalent in patients with advanced, unresectable, or high-grade disease (2). Rhabdomyosarcoma is the most common pediatric soft-tissue sarcoma and the third most common extracranial solid tumor in children following neuroblastoma and Wilm's tumor, with an annual incidence of 4 to 7 cases per million children under the age of 16 years (3,4). Multimodal treatment has significantly improved survival to approximately 70%.…”

Section: Introductionmentioning

confidence: 99%

Nab-Paclitaxel Is an Active Drug in Preclinical Model of Pediatric Solid Tumors

Zhang

Marrano

Kumar

et al. 2013

Clinical Cancer Research

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Purpose: To investigate the antitumor effect of nab-paclitaxel, an albumin-stabilized nanoparticle formulation of paclitaxel, on pediatric solid tumor models.Experimental Design: A panel of three rhabdomyosarcoma, one osteosarcoma and seven neuroblastoma cell lines were exposed to increasing concentrations of nab-paclitaxel in vitro. Cell viability was evaluated using the Alamar Blue Assay. Antitumor effect was further assessed in vivo in NOD/SCID xenograft and metastatic neuroblastoma mouse models. Tumor sections were analyzed by immunohistochemistry for cleaved caspase-3 and phospho-histone H3. Plasma and intratumoral paclitaxel concentrations were measured by liquid chromatography-mass spectrometry. Ratio of intratumoral and plasma concentration was compared between nab-paclitaxel and paclitaxel treatment groups.Results: Nab-paclitaxel displayed significant cytotoxicity against most pediatric solid tumor cell lines in vitro in a dose-dependent manner. In vivo, nab-paclitaxel showed antitumor activity in both rhabdomyosarcoma (RH4 and RD) and neuroblastoma [SK-N-BE(2) and CHLA-20] xenograft models. In the SK-N-BE (2) metastatic model, nab-paclitaxel treatment significantly extended animal survival compared with control (P < 0.01). Nab-paclitaxel treatment induced tumor cell-cycle arrest and apoptosis in vivo. In the RH4 model, increased local relapse-free intervals were observed with nab-paclitaxel treatment (37.7 AE 3.2 days) comparing with paclitaxel (13.6 AE 2.07 days). Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant and remained responsive to nab-paclitaxel. Mechanistically, a higher tumor/plasma paclitaxel drug ratio in favor of nab-paclitaxel was observed.Conclusions: Nab-paclitaxel showed significant antitumor activity against all pediatric solid tumors associated with an enhanced drug intratumor delivery. Furthermore, testing of nab-paclitaxel in pediatric solid-tumor patient population is under development.

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“…PAX-FOXO1-positive RMS (clinically termed alveolar RMS) is notoriously aggressive (4). The PAX-FOXO1 transcription factor (also known as PAX-FKHR) is generated by chromosomal translocations that fuse a PAX gene (PAX3 on chromosome 2 or PAX7 on chromosome 1) to FOXO1 on chromosome 13.…”

Section: Introductionmentioning

confidence: 99%

Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma

Avirneni-Vadlamudi¹,

Galindo²,

Endicott³

et al. 2012

J. Clin. Invest.

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Rhabdomyosarcoma (RMS) is a malignancy of muscle myoblasts, which fail to exit the cell cycle, resist terminal differentiation, and are blocked from fusing into syncytial skeletal muscle. In some patients, RMS is caused by a translocation that generates the fusion oncoprotein PAX-FOXO1, but the underlying RMS pathogenetic mechanisms that impede differentiation and promote neoplastic transformation remain unclear. Using a Drosophila model of PAX-FOXO1-mediated transformation, we show here that mutation in the myoblast fusion gene rolling pebbles (rols) dominantly suppresses PAX-FOXO1 lethality. Further analysis indicated that PAX-FOXO1 expression caused upregulation of rols, which suggests that Rols acts downstream of PAX-FOXO1. In mammalian myoblasts, gene silencing of Tanc1, an ortholog of rols, revealed that it is essential for myoblast fusion, but is dispensable for terminal differentiation. Misexpression of PAX-FOXO1 in myoblasts upregulated Tanc1 and blocked differentiation, whereas subsequent reduction of Tanc1 expression to native levels by RNAi restored both fusion and differentiation. Furthermore, decreasing human TANC1 gene expression caused RMS cancer cells to lose their neoplastic state, undergo fusion, and form differentiated syncytial muscle. Taken together, these findings identify misregulated myoblast fusion caused by ectopic TANC1 expression as a RMS neoplasia mechanism and suggest fusion molecules as candidates for targeted RMS therapy.

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Childhood Rhabdomyosarcoma: New Insight on Biology and Treatment

Cited by 91 publications

References 48 publications

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Nab-Paclitaxel Is an Active Drug in Preclinical Model of Pediatric Solid Tumors

Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma

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