Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

Oesch, Susanne; Walter, Dagmar; Wachtel, Marco; Prêtre, Kathya; Salazar, María; Guzmán, Manuel; Velasco, Guillermo; Schäfer, Beat W.

doi:10.1158/1535-7163.mct-08-1147

Cited by 50 publications

(26 citation statements)

References 36 publications

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“…As seen in Fig. 2C Previously, it has been reported that treatment with the CNR1 agonist Met-F-AEA can induce apoptosis in ARMS cell lines (32). Treatment with either 3 or 30 mmol/L Met-F-AEA for 24 hours failed to induce any increase in apoptosis over that These results show that although CNR1 is grossly upregulated by PAX3-FOXO1 it does not play an appreciable role in enhanced proliferation, inhibited differentiation, or enhanced transformation seen with PAX3-FOXO1 expression in primary myoblasts.…”

Section: Cnr1 Upregulation Does Not Contribute To Proliferation Diffmentioning

confidence: 64%

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PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis

2011

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Alveolar rhabdomyosarcoma (ARMS) is a muscle-derived childhood tumor characterized by production of oncogenic PAX3/7-FOXO1 chimeric transcription factors. While downstream targets of the PAX3-FOXO1 oncoprotein in ARMS have been defined, the functional relevance of these targets is unclear. Here, we show that upregulation of the cannabinoid receptor 1 (Cnr1/Cb1) by PAX3-FOXO1 in mouse primary myoblasts and ARMS cell lines, contributes to PAX3-FOXO1 phenotypes, both in vivo and in vitro. In primary myoblasts, Cnr1 was dispensable for PAX3-FOXO1 to mediate cell proliferation, differentiation, or transformation; however, Cnr1 function was essential to increase the invasive capacity conferred by PAX3-FOXO1 overexpression in these cells. Genetic or pharmacologic abrogation of Cnr1 inhibited the enhanced basement membrane invasion induced by PAX3-FOXO1. Cnr1 loss by either route also dramatically reduced lung metastasis formation. Taken together, our findings strongly implicate Cnr1 as a novel tractable target to inhibit ARMS invasion and metastasis. Cancer Res; 71(24); 7471-80. Ó2011 AACR.

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Section: Cnr1 Upregulation Does Not Contribute To Proliferation Diffmentioning

confidence: 64%

“…Recently, Oesch and colleagues (32) reported that treatment of ARMS cell lines, RH4 in particular, with Cnr1 agonists induced apoptosis. We did not find induction of apoptosis in RH4 with treatment of MET-F-AEA [ Fig.…”

Section: Discussionmentioning

confidence: 99%

PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis

2011

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“…inhibition of cnr1 with increased concentrations of aM28, an antagonistic inhibitor did not impair cell viability of the rMS cells (rh30 and rD) at concentrations below 40 µM (unpublished own data). However, agonists of cnr1 reduced rMS cell proliferation (23).…”

Section: Discussionmentioning

confidence: 97%

Differential expression of invasion promoting genes in childhood rhabdomyosarcoma

Armeanu–Ebinger

Bonin²,

Häbig³

et al. 2011

Int J Oncol

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Abstract. expression profiling of tumor tissue allows a systematic search for targeted therapies and offers relevant prognostic information. Molecular studies on rhabdomyosarcoma (RMS) revealed a more differentiated classification than the histological subgrouping into embryonal (rMe) and alveolar (RMA) rhabdomyosarcoma, and reflected the chromosomal aberrations found in rMS. We addressed biological processes like cell migration and emerging drug resistance by expression profiling to identify mechanisms of metastasic invasion and differential response to chemotherapy in rMS. gene expression analysis was performed in 19 rMS samples using the affymetrix u133 Plus2 array. Validation of target genes was performed by qrt-Pcr. Data were analyzed using Pathway analysis software. involvement of these genes in invasion processes was evaluated in knock-down experiments using specific interference rna and Matrigel tM invasion assay. in rMa tissues 211 of 534 genes were overexpressed, in rMe tissues 323 genes were overexpressed. Pathway analysis software identified a group of genes involved in cell growth, morphology and motility. in patients with distant metastases especially transcription factors such as foXf1 and lMo4 showed a high expression, which were described as determinants of tumor cell migration. Down-regulation of these factors inhibited the invasion of rMS cells >10-fold. Microarray technology is a powerful method not only to classify rMS samples, but also to identify major regulatory processes. functional evaluation of lMo4 and foXf1 identified targets of a molecular network for preventing metastatic invasion in rMS.

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“…RAS Mutations [12,13] SHH Activation [14] IGF2 Loss of imprinting [15,16] EGFR Overexpression [17,18] translocation-positive RMS PAX/FKHR Translocation [11,19] NMYC Amplification [20] FGFR4 Mutations [21,22] CB1 - [23] IL4R…”

Section: Translocation-negative Rmsmentioning

confidence: 99%

Multidisciplinary management of childhood sarcoma: time to expand

Schäfer

Niggli

2010

Expert Review of Anticancer Therapy

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"…our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups."Sarcomas are a heterogeneous group of tumors. In the last 20 years, the finding of specific acquired chromosomal alterations in sarcomas has helped, in many cases, to understand their underlying genetic basis. Each of the various recurrent chromosomal translocations in sarcomas ultimately results in the creation of a novel chimeric or fusion gene. With the discovery of these new chromosomal alterations in sarcomas, and subsequently of the fusion genes, it was believed that remarkable progress would be possible in the treatment approach for these tumors. Certainly, our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups. However, whether this information has also translated into a better treatment approach is questionable. In children, rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor. Although combined treatment modalities including surgery, chemotherapy and/or radiotherapy have increased overall survival in many RMSs and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse.Furthermore, another important concern is the side effects of conventional chemotherapy and especially radio therapy. Since most current therapies are not specifically targeted to tumor cells, a variety of normal cells in the body may also be affected by these therapeutic modalities, resulting in undesired and long-term side effects in the developing child."Although combined treatment modalities … have increased overall survival in many rhabdomyosarcomas and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse."Optimization of chemotherapy has certainly brought some improvement but it is unlikely to deliver a real breakthrough in the therapeutic approach. Combination therapies including vincristine, dactinomycin and cyclophosphamide or ifosfamide can be considered as the backbone of current treatment protocols. Other antineoplastic agents including doxorubicin, cisplatin, carboplatin, etoposide, topotecan, irinotecan, melphalan and methotrexate are active against RMS and have been combined in various combinations with backbone drugs. The overall survival rate in non-metastatic RMS has reached approximately 70%. However, substantial differences can be observed according to tumor site and clinical stage, ranging from approximately 60%, for example, in RMS of the limbs, to 90% or higher in orbital RMS or in genitourinary and nonbladder

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Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

Cited by 50 publications

References 36 publications

PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis

PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis

Differential expression of invasion promoting genes in childhood rhabdomyosarcoma

Multidisciplinary management of childhood sarcoma: time to expand

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