Browsing by Author "Staedtke, Verena"

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    Correction: Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
    (Springer Nature, 2022) Gampala, Silpa; Shah, Fenil; Zhang, Chi; Rhodes, Steven D.; Babb, Olivia; Grimard, Michelle; Wireman, Randall S.; Rad, Ellie; Calver, Brian; Bai, Ren-Yuan; Staedtke, Verena; Hulsey, Emily L.; Saadatzadeh, M. Reza; Pollok, Karen E.; Tong, Yan; Smith, Abbi E.; Clapp, D. Wade; Tee, Andrew R.; Kelley, Mark R.; Fishel, Melissa L.; Pediatrics, School of Medicine
    Correction to: British Journal of Cancer 10.1038/s41416-021-01270-8, published online 03 March 2021 The original version of this article unfortunately contained an error in Figure 4, specifically: Figure 4f: the middle cell image was originally a duplicate of the middle cell image from Fig. 4d; the correct image is now used. The corrected figure is displayed below. The correction does not have any effect on the final conclusions of the paper. The original article has been corrected.
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    Existing and Developing Preclinical Models for Neurofibromatosis Type 1–Related Cutaneous Neurofibromas
    (Elsevier, 2023) Staedtke, Verena; Topilko, Piotr; Le, Lu Q.; Grimes, Kevin; Largaespada, David A.; Cagan, Ross L.; Steensma, Matthew R.; Stemmer-Rachamimov, Anat; Blakeley, Jaishri O.; Rhodes, Steven D.; Ly, Ina; Romo, Carlos G.; Lee, Sang Y.; Serra, Eduard; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.
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    Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
    (Springer Nature, 2021) Gampala, Silpa; Shah, Fenil; Zhang, Chi; Rhodes, Steven D.; Babb, Olivia; Grimard, Michelle; Wireman, Randall S.; Rad, Ellie; Calver, Brian; Bai, Ren-Yuan; Staedtke, Verena; Hulsey, Emily L.; Saadatzadeh, M. Reza; Pollok, Karen E.; Tong, Yan; Smith, Abbi E.; Clapp, D. Wade; Tee, Andrew R.; Kelley, Mark R.; Fishel, Melissa L.; Pediatrics, School of Medicine
    Background: MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) redox function. A first-generation Ref-1 inhibitor, APX3330, is being tested in cancer clinical trials and could be applied to MPNST. Methods: We characterised Ref-1 and p-STAT3 expression in various MPNST models. Tumour growth, as well as biomarkers of apoptosis and signalling pathways, were measured by qPCR and western blot following treatment with inhibitors of Ref-1 or STAT3. Results: MPNSTs from Nf1-Arfflox/floxPostnCre mice exhibit significantly increased positivity of p-STAT3 and Ref-1 expression when malignant transformation occurs. Inhibition of Ref-1 or STAT3 impairs MPNST growth in vitro and in vivo and induces apoptosis. Genes highly expressed in MPNST patients are downregulated following inhibition of Ref-1 or STAT3. Several biomarkers downstream of Ref-1 or STAT3 were also downregulated following Ref-1 or STAT3 inhibition. Conclusions: Our findings implicate a unique therapeutic approach to target important MPNST signalling nodes in sarcomas using new first-in-class small molecules for potential translation to the clinic.
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    Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors
    (Springer Nature, 2019-06) Bai, Ren-Yuan; Esposito, Dominic; Tam, Ada J.; McCormick, Frank; Riggins, Gregory J.; Clapp, D. Wade; Staedtke, Verena; Pediatrics, School of Medicine
    Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs). We demonstrated that several AAV serotypes achieved favorable transduction efficacies in those cells and a membrane-targeting GRD fused with an H-Ras C-terminal motif (C10) dramatically inhibited the Ras pathway and MPNST cells in a NF1-specific manner. Our results opened up a venue of gene replacement therapy in NF1-related tumors.
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    RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights
    (Elsevier, 2023) Rhodes, Steven D.; McCormick, Frank; Cagan, Ross L.; Bakker, Annette; Staedtke, Verena; Ly, Ina; Steensma, Matthew R.; Lee, Sang Y.; Romo, Carlos G.; Blakeley, Jaishri O.; Sarin, Kavita Y.; Pediatrics, School of Medicine
    Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.