PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma

Taniguchi, Eiichi; Nishijo, Koichi; McCleish, Amanda T.; Michalek, Joel E.; Grayson, Mitchell H.; Infante, Anthony J.; Abboud, Hanna E.; LeGallo, Robin D.; Qualman, Stephen J.; Rubin, Brian P.; Keller, Charles

doi:10.1038/onc.2008.255

Cited by 82 publications

(112 citation statements)

References 28 publications

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“…These findings were particularly surprising, as PDGFRa is readily detectable in rhabdomyosarcoma clinical specimens by qPCR or IHC and PDGFRA is a transcriptional target of the fusion protein driving alveolar rhabdomyosarcoma (PAX3-FOXO; refs. 20,22,26). Similarly, the Ewing sarcoma PDX models evaluated in this study were negative for PDGFC expression, despite previous work identifying PDGFC as a target gene of the EWS-FLI1 fusion transcription factor (42).…”

Section: Discussionmentioning

confidence: 41%

“…S1B). Surprisingly, although previous studies reported robust PDGFRa expression in human and murine rhabdomyosarcoma (20,28), low levels of PDGFRA and PDGFRB transcript were detected in the alveolar rhabdomyosarcoma cell line SJCRH30 (Fig. 1A).…”

Section: Expression Of Pdgf Pathway Components Is Detected In Severalmentioning

confidence: 59%

“…Although the prevalence of PDGFRA genetic aberrations in pediatric cancer is reported to be only about 2% (19), members of the PDGF pathway are highly expressed in several subtypes of pediatric bone and soft tissue tumors, including rhabdomyosarcoma (20,21), synovial sarcoma (22), osteogenic sarcoma (23), Ewing sarcoma (24), and MRT (25). In addition, PDGFRa expression is linked to adverse outcomes in pediatric patients with rhabdomyosarcoma (26).…”

Section: Introductionmentioning

confidence: 99%

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Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

Lowery

Blosser

Dowless

et al. 2018

Clinical Cancer Research

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Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors. Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor. Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin. Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847–57. ©2017 AACR.

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Section: Discussionmentioning

confidence: 41%

Section: Expression Of Pdgf Pathway Components Is Detected In Severalmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

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Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

Lowery

Blosser

Dowless

et al. 2018

Clinical Cancer Research

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“…In turn, the PDGFRs are involved in multiple malignant processes through activating mutations or driving oncogenic signaling pathways in both epithelial and hematologic malignancies (14)(15)(16). In aRMS, PDGFRα is a transcriptional target of a translocation-mediated fusion gene of PAX3 and FOXO1 (PAX3:FOXO1) and a therapeutic target in preclinical studies using the small molecule inhibitor imatinib or antibodymediated receptor blockade (17). Although cross-talk between the PDGFRs and the Eph receptors has not been directly investigated in tumorigenesis, evidence of an existing functional interface between the receptors has been implicated in select nonmalignant biological systems (18).…”

mentioning

confidence: 99%

PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma

Aslam

Abraham

Mansoor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Alveolar rhabdomyosarcoma (aRMS) is an aggressive myogenic childhood malignancy, not infrequently presenting as incurable metastatic disease. To identify therapeutic targets, we performed an unbiased tyrosine kinome RNA interference screen in primary cell cultures from a genetically engineered, conditional mouse model of aRMS. We identified ephrin receptor B4 (EphB4) as a target that is widely expressed in human aRMS and that portends a poor clinical outcome in an expression level-dependent manner. We also uncovered cross-talk of this ephrin receptor with another receptor tyrosine kinase, PDGFRβ, which facilitates PDGF ligand-dependent, ephrin ligand-independent activation of EphB4 converging on the Akt and Erk1/2 pathways. Conversely, EphB4 activation by its cognate ligand, EphrinB2, did not stimulate PDGFRβ; instead, apoptosis was paradoxically induced. Finally, we showed that smallmolecule inhibition of both PDGFRβ and EphB4 by dasatinib resulted in a significant decrease in tumor cell viability in vitro, as well as decreased tumor growth rate and significantly prolonged survival in vivo. To our knowledge, these results are the first to identify EphB4 and its cross-talk with PDGFRβ as unexpected vital determinants of tumor cell survival in aRMS, with EphB4 at the crux of a bivalent signaling node that is either mitogenic or proapoptotic.sarcoma | pediatric | muscle

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“…However, results from these studies are rather conflicting. Some studies demonstrated that imatinib, which inhibits both PDGFR and c-kit, is able to inhibit growth of Ewing's sarcoma, osteosarcoma or rhabdomyosarcoma cells in vitro and as xenografts in vivo with a high IC 50 of 6-15 μM (34,36,(43)(44)(45). In contrast, IC 50 -concentrations of imatinib necessary to inhibit ligand induced phosphorylation of PDGFR and c-kit were in the range of 0.1-0.5 μM (44,46).…”

Section: Receptor Tyrosine Kinasesmentioning

confidence: 98%

Targets for cancer therapy in childhood sarcomas

Wachtel¹,

Schäfer²

2010

Cancer Treatment Reviews

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Development of chemotherapeutic treatment modalities resulted in a dramatic increase in the survival of children with many types of cancer. Still, in case of some pediatric cancer entities including rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma, survival of patients remains dismal and novel treatment approaches are urgently needed. Therefore, based on the concept of targeted therapy, numerous potential targets for the treatment of these cancers have been evaluated pre-clinically or in some cases even clinically during the last decade. This review gives an overview over many different potential therapeutic targets for treatment of these childhood sarcomas, including receptor tyrosine kinases, intracellular signaling molecules, cell cycle and apoptosis regulators, proteasome, hsp90, histone deacetylases, angiogenesis regulators and sarcoma specific fusion proteins. The large number of potential therapeutic targets suggests that improved comparability of pre-clinical models might be necessary to prioritize the most effective ones for future clinical trials. Targets for Cancer Therapy in Childhood Sarcomas AbstractDevelopment of chemotherapeutic treatment modalities resulted in a dramatic increase in the survival of children with many types of cancer. Still, in case of some pediatric cancer entities including rhabdomyosarcoma, osteosarcoma and Ewing´s sarcoma, survival of patients remains dismal and novel treatment approaches are urgently needed. Therefore, based on the concept of targeted therapy, numerous potential targets for the treatment of these cancers have been evaluated preclinically or in some cases even clinically during the last decade. This review gives an overview over many different potential therapeutic targets for treatment of these childhood sarcomas, including receptor tyrosine kinases, intracellular signaling molecules, cell cycle and apoptosis regulators, proteasome, hsp90, histone deacetylases, angiogenesis regulators and sarcoma specific fusion-proteins. The large number of potential therapeutic targets suggests that improved comparability of preclinical models might be necessary to prioritize the most effective ones for future clinical trials.

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PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma

Cited by 82 publications

References 28 publications

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma

Targets for cancer therapy in childhood sarcomas

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