Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma

Alijaj, Nagjie; Moutel, Sandrine; Gouveia, Zélia; Gray, Maxim; Roveri, Maurizio; Dzhumashev, Dzhangar; Weber, Florian; Meier, Gianmarco; Luciani, Paola; Rößler, Jochen; Schäfer, Beat W.; Perez, Franck; Bernasconi, Michele

doi:10.3390/cancers12113313

Cited by 22 publications

(22 citation statements)

References 56 publications

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“…A single domain antibody is one of the active targeting moieties and have advantages of high physicochemical stability, rapid tissue penetration, and facile genetic manipulation [ 65 ]. Single domain antibodies have been recently used in liposome research which is limited in vitro experiments [ 66 – 68 ]. Attaching the active targeting moiety to the LAL, which already showed the high passive tumor targeting, it is expected to have a synergistic tumor targeting efficiency.…”

Section: Resultsmentioning

confidence: 99%

Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy

et al. 2021

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Background Photothermal therapy (PTT) is an emerging anti-cancer therapeutic strategy that generates hyperthermia to ablate cancer cells under laser irradiation. Gold (Au) coated liposome (AL) was reported as an effective PTT agent with good biocompatibility and excretory property. However, exposed Au components on liposomes can cause instability in vivo and difficulty in further functionalization. Results Herein, we developed a theranostic dual-layered nanomaterial by adding liposomal layer to AL (LAL), followed by attaching polyethylene glycol (PEG) and radiolabeling. Functionalization with PEG improves the in vivo stability of LAL, and radioisotope labeling enables in vivo imaging of LAL. Functionalized LAL is stable in physiological conditions, and 64Cu labeled LAL (64Cu-LAL) shows a sufficient blood circulation property and an effective tumor targeting ability of 16.4%ID g−1 from in vivo positron emission tomography (PET) imaging. Also, intravenously injected LAL shows higher tumor targeting, temperature elevation in vivo, and better PTT effect in orthotopic breast cancer mouse model compared to AL. The tumor growth inhibition rate of LAL was 3.9-fold higher than AL. Conclusion Based on these high stability, in vivo imaging ability, and tumor targeting efficiency, LAL could be a promising theranostic PTT agent. Graphic Abstract

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Section: Resultsmentioning

confidence: 99%

Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy

et al. 2021

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“…Once immobilized on the surface of vincristine-loaded liposomes, these single-domain antibodies were able to be recognized by FGFR4 expressing RMS cells and internalized. Moreover, one of these antibodies was used to generate CAR T cells targeting FGFR4 and was shown to mediate significant antitumor activity against FGFR4-expressing RMS cells in vitro [ 66 ].…”

Section: Fgfr Inhibition In the Therapy Of Gist And Stsmentioning

confidence: 99%

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Napolitano

Ostler

Jones

et al. 2021

Cells

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Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.

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“…Glypican 3 (GPC3) is another promising target for CAR T cell therapy. GPC3 expression is reported in rhabdomyosarcoma and undifferentiated soft tissue sarcomas [ 39 , 40 , 42 , 43 ]. Two phase I clinical trials that are not yet recruiting, will be open to young patients with GPC3 tumors (NCT04377932; NCT04715191).…”

Section: Car T Cells In Clinical Trials For Pediatric Sarcomasmentioning

confidence: 99%

Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma

Terry

Meyran

Fleuren

et al. 2021

Cancers

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Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.

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Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma

Cited by 22 publications

References 56 publications

Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy

Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma

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