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

Velina S. Atanasova, Celine Pourreyron, Mehdi Farshchian, Michael E. Lawler, Christian A. Brown, Stephen Watt, Sheila Wright, Michael Warkala, Christina Guttmann-Gruber, Josefina Pinon-Hofbauer, Ignacia Fuentes, Marco Prisco, Elham Rashidghamat, Cristina Has, Julio C. Salas-Alanis, Francis Palisson, Alain Hovnanian, John A. McGrath, Jemima Mellerio, Johann W. BauerAndrew P. South

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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.

Original languageEnglish
Pages (from-to)3384-3391
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number11
Early online date7 Mar 2019
DOIs
Publication statusPublished - Jun 2019

Fingerprint

Epidermolysis Bullosa Dystrophica
Squamous Cell Carcinoma
Therapeutics
Skin
ON 01910
Phase II Clinical Trials
Inborn Genetic Diseases
Vinblastine
Mitogen-Activated Protein Kinase Kinases
Growth
Keratinocytes
Heterografts
Microtubules
Small Interfering RNA
Cause of Death
Research Design
Apoptosis

Cite this

Atanasova, Velina S. ; Pourreyron, Celine ; Farshchian, Mehdi ; Lawler, Michael E. ; Brown, Christian A. ; Watt, Stephen ; Wright, Sheila ; Warkala, Michael ; Guttmann-Gruber, Christina ; Pinon-Hofbauer, Josefina ; Fuentes, Ignacia ; Prisco, Marco ; Rashidghamat, Elham ; Has, Cristina ; Salas-Alanis, Julio C. ; Palisson, Francis ; Hovnanian, Alain ; McGrath, John A. ; Mellerio, Jemima ; Bauer, Johann W. ; South, Andrew P. / Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 11. pp. 3384-3391.
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title = "Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma",
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.",
author = "Atanasova, {Velina S.} and Celine Pourreyron and Mehdi Farshchian and Lawler, {Michael E.} and Brown, {Christian A.} and Stephen Watt and Sheila Wright and Michael Warkala and Christina Guttmann-Gruber and Josefina Pinon-Hofbauer and Ignacia Fuentes and Marco Prisco and Elham Rashidghamat and Cristina Has and Salas-Alanis, {Julio C.} and Francis Palisson and Alain Hovnanian and McGrath, {John A.} and Jemima Mellerio and Bauer, {Johann W.} and South, {Andrew P.}",
note = "Funding - This work was supported by DEBRA International – funded by DEBRA UK (grant to APS, and grant to APS, JWB, and JEM) and the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Congressionally Directed Medical Research Program under Award No. (W81XWH18-1-0382 to APS). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. M.F. is supported by the Sigrid Juse´lius Foundation, Orion Research Foundation, and the Finnish Society of Dermatology",
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month = "6",
doi = "10.1158/1078-0432.CCR-18-2661",
language = "English",
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pages = "3384--3391",
journal = "Clinical Cancer Research",
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Atanasova, VS, Pourreyron, C, Farshchian, M, Lawler, ME, Brown, CA, Watt, S, Wright, S, Warkala, M, Guttmann-Gruber, C, Pinon-Hofbauer, J, Fuentes, I, Prisco, M, Rashidghamat, E, Has, C, Salas-Alanis, JC, Palisson, F, Hovnanian, A, McGrath, JA, Mellerio, J, Bauer, JW & South, AP 2019, 'Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma', Clinical Cancer Research, vol. 25, no. 11, pp. 3384-3391. https://doi.org/10.1158/1078-0432.CCR-18-2661

Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma. / Atanasova, Velina S.; Pourreyron, Celine; Farshchian, Mehdi; Lawler, Michael E.; Brown, Christian A.; Watt, Stephen; Wright, Sheila; Warkala, Michael; Guttmann-Gruber, Christina; Pinon-Hofbauer, Josefina; Fuentes, Ignacia; Prisco, Marco; Rashidghamat, Elham; Has, Cristina; Salas-Alanis, Julio C.; Palisson, Francis; Hovnanian, Alain; McGrath, John A.; Mellerio, Jemima; Bauer, Johann W.; South, Andrew P. (Lead / Corresponding author).

In: Clinical Cancer Research, Vol. 25, No. 11, 06.2019, p. 3384-3391.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma

AU - Atanasova, Velina S.

AU - Pourreyron, Celine

AU - Farshchian, Mehdi

AU - Lawler, Michael E.

AU - Brown, Christian A.

AU - Watt, Stephen

AU - Wright, Sheila

AU - Warkala, Michael

AU - Guttmann-Gruber, Christina

AU - Pinon-Hofbauer, Josefina

AU - Fuentes, Ignacia

AU - Prisco, Marco

AU - Rashidghamat, Elham

AU - Has, Cristina

AU - Salas-Alanis, Julio C.

AU - Palisson, Francis

AU - Hovnanian, Alain

AU - McGrath, John A.

AU - Mellerio, Jemima

AU - Bauer, Johann W.

AU - South, Andrew P.

N1 - Funding - This work was supported by DEBRA International – funded by DEBRA UK (grant to APS, and grant to APS, JWB, and JEM) and the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Congressionally Directed Medical Research Program under Award No. (W81XWH18-1-0382 to APS). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. M.F. is supported by the Sigrid Juse´lius Foundation, Orion Research Foundation, and the Finnish Society of Dermatology

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

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DO - 10.1158/1078-0432.CCR-18-2661

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JO - Clinical Cancer Research

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