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Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.

Show simple item record Atanasova, Velina S. Pourreyron, Celine Farshchian, Mehdi Christian A., Brown IV Watt, Stephen A. Wright, Sheila Warkala, Michael Guttmann-Gruber, Christina Piñón Hofbauer, Josefina Fuentes, Ignacia Prisco, Marco Rashidghamat, Elham Has, Cristina Palisson, Francis Hovnanian, Alain McGrath, John A. Mellerio, Jemima E. Bauer, Johann South, Andrew P. 2020-04-02T19:37:13Z 2020-04-02T19:37:13Z 2019
dc.identifier.citation Clin Cancer Res. 2019 Jun 1;25(11):3384-3391
dc.description.abstract Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.
dc.format.extent 30 p.
dc.language.iso en
dc.subject AKT
dc.subject CRAF
dc.subject RAS
dc.subject Squamous cell carcinoma
dc.subject PLK1
dc.subject Recessive dystrophic epidermolysis bullosa
dc.title Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
dc.type Article

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