Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair

Ana Alicia López-Iglesias, Ana B. Herrero, Marta Chesi, Laura San-Segundo, Lorena González-Méndez, Susana Hernández-García, Irena Misiewicz-Krzeminska, Dalia Quwaider, Montserrat Martín-Sánchez, Daniel Primo, Teresa Paíno, Peter Leif Bergsagel, Thomas Mehrling, Marcos González-Díaz, Jesús F. San-Miguel, María Victoria Mateos, Norma C. Gutiérrez, Mercedes Garayoa, Enrique M. Ocio

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. Methods: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. Results: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6-4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk∗MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. Conclusion: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.

Original languageEnglish (US)
Article number127
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
StatePublished - Jun 20 2017

Fingerprint

DNA Repair
DNA Damage
Multiple Myeloma
Cell Line
Pharmaceutical Preparations
Recombinational DNA Repair
Proteasome Inhibitors
Histone Deacetylase Inhibitors
Melphalan
Plasmacytoma
EDO-S101
Bendamustine Hydrochloride
Tubulin
Histones
Inhibitory Concentration 50
Plasmids
Therapeutics
Genome
Survival
DNA

Keywords

  • Bendamustine
  • DNA damage
  • EDO-S101
  • Homologous recombination
  • Multiple myeloma

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair. / López-Iglesias, Ana Alicia; Herrero, Ana B.; Chesi, Marta; San-Segundo, Laura; González-Méndez, Lorena; Hernández-García, Susana; Misiewicz-Krzeminska, Irena; Quwaider, Dalia; Martín-Sánchez, Montserrat; Primo, Daniel; Paíno, Teresa; Bergsagel, Peter Leif; Mehrling, Thomas; González-Díaz, Marcos; San-Miguel, Jesús F.; Mateos, María Victoria; Gutiérrez, Norma C.; Garayoa, Mercedes; Ocio, Enrique M.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 127, 20.06.2017.

Research output: Contribution to journalArticle

López-Iglesias, AA, Herrero, AB, Chesi, M, San-Segundo, L, González-Méndez, L, Hernández-García, S, Misiewicz-Krzeminska, I, Quwaider, D, Martín-Sánchez, M, Primo, D, Paíno, T, Bergsagel, PL, Mehrling, T, González-Díaz, M, San-Miguel, JF, Mateos, MV, Gutiérrez, NC, Garayoa, M & Ocio, EM 2017, 'Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair', Journal of Hematology and Oncology, vol. 10, no. 1, 127. https://doi.org/10.1186/s13045-017-0495-y
López-Iglesias, Ana Alicia ; Herrero, Ana B. ; Chesi, Marta ; San-Segundo, Laura ; González-Méndez, Lorena ; Hernández-García, Susana ; Misiewicz-Krzeminska, Irena ; Quwaider, Dalia ; Martín-Sánchez, Montserrat ; Primo, Daniel ; Paíno, Teresa ; Bergsagel, Peter Leif ; Mehrling, Thomas ; González-Díaz, Marcos ; San-Miguel, Jesús F. ; Mateos, María Victoria ; Gutiérrez, Norma C. ; Garayoa, Mercedes ; Ocio, Enrique M. / Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair. In: Journal of Hematology and Oncology. 2017 ; Vol. 10, No. 1.
@article{da61ae34daa94251a37fd8478cf9e9d4,
title = "Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair",
abstract = "Background: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. Methods: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. Results: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6-4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk∗MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. Conclusion: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.",
keywords = "Bendamustine, DNA damage, EDO-S101, Homologous recombination, Multiple myeloma",
author = "L{\'o}pez-Iglesias, {Ana Alicia} and Herrero, {Ana B.} and Marta Chesi and Laura San-Segundo and Lorena Gonz{\'a}lez-M{\'e}ndez and Susana Hern{\'a}ndez-Garc{\'i}a and Irena Misiewicz-Krzeminska and Dalia Quwaider and Montserrat Mart{\'i}n-S{\'a}nchez and Daniel Primo and Teresa Pa{\'i}no and Bergsagel, {Peter Leif} and Thomas Mehrling and Marcos Gonz{\'a}lez-D{\'i}az and San-Miguel, {Jes{\'u}s F.} and Mateos, {Mar{\'i}a Victoria} and Guti{\'e}rrez, {Norma C.} and Mercedes Garayoa and Ocio, {Enrique M.}",
year = "2017",
month = "6",
day = "20",
doi = "10.1186/s13045-017-0495-y",
language = "English (US)",
volume = "10",
journal = "Journal of Hematology and Oncology",
issn = "1756-8722",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair

AU - López-Iglesias, Ana Alicia

AU - Herrero, Ana B.

AU - Chesi, Marta

AU - San-Segundo, Laura

AU - González-Méndez, Lorena

AU - Hernández-García, Susana

AU - Misiewicz-Krzeminska, Irena

AU - Quwaider, Dalia

AU - Martín-Sánchez, Montserrat

AU - Primo, Daniel

AU - Paíno, Teresa

AU - Bergsagel, Peter Leif

AU - Mehrling, Thomas

AU - González-Díaz, Marcos

AU - San-Miguel, Jesús F.

AU - Mateos, María Victoria

AU - Gutiérrez, Norma C.

AU - Garayoa, Mercedes

AU - Ocio, Enrique M.

PY - 2017/6/20

Y1 - 2017/6/20

N2 - Background: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. Methods: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. Results: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6-4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk∗MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. Conclusion: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.

AB - Background: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. Methods: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. Results: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6-4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk∗MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. Conclusion: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.

KW - Bendamustine

KW - DNA damage

KW - EDO-S101

KW - Homologous recombination

KW - Multiple myeloma

UR - http://www.scopus.com/inward/record.url?scp=85020877308&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020877308&partnerID=8YFLogxK

U2 - 10.1186/s13045-017-0495-y

DO - 10.1186/s13045-017-0495-y

M3 - Article

VL - 10

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

SN - 1756-8722

IS - 1

M1 - 127

ER -