Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

N Bharathy; Noah Berlow; E Wang; J Abraham; T P Settelmeyer; J E Hooper; M N Svalina; Z Bajwa; M W Goros; B S Hernandez; J E Wolff; Ranadip Pal; A M Davies; A Ashok; D Bushby; M Mancini; C Noakes; N C Goodwin; P Ordentlich; J Keck; D S Hawkins; E R Rudzinski; A Mansoor; T J Perkins; C R Vakoc; J E Michalek; C Keller

Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

N Bharathy, Noah Berlow, E Wang, J Abraham, T P Settelmeyer, J E Hooper, M N Svalina, Z Bajwa, M W Goros, B S Hernandez, J E Wolff, Ranadip Pal, A M Davies, A Ashok, D Bushby, M Mancini, C Noakes, N C Goodwin, P Ordentlich, J KeckD S Hawkins, E R Rudzinski, A Mansoor, T J Perkins, C R Vakoc, J E Michalek, C Keller

Electrical and Computer Engineering

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

Original language	English
Pages (from-to)	12
Journal	Default journal
State	Published - May 21 2019

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Bharathy, N., Berlow, N., Wang, E., Abraham, J., Settelmeyer, T. P., Hooper, J. E., Svalina, M. N., Bajwa, Z., Goros, M. W., Hernandez, B. S., Wolff, J. E., Pal, R., Davies, A. M., Ashok, A., Bushby, D., Mancini, M., Noakes, C., Goodwin, N. C., Ordentlich, P., ... Keller, C. (2019). Preclinical rationale for entinostat in embryonal rhabdomyosarcoma. Default journal, 12.

@article{e83a92b639f543ff93c0406bbd0ab59d,

title = "Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.",

abstract = "Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic {"}allografts,{"} although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.",

author = "N Bharathy and Noah Berlow and E Wang and J Abraham and Settelmeyer, {T P} and Hooper, {J E} and Svalina, {M N} and Z Bajwa and Goros, {M W} and Hernandez, {B S} and Wolff, {J E} and Ranadip Pal and Davies, {A M} and A Ashok and D Bushby and M Mancini and C Noakes and Goodwin, {N C} and P Ordentlich and J Keck and Hawkins, {D S} and Rudzinski, {E R} and A Mansoor and Perkins, {T J} and Vakoc, {C R} and Michalek, {J E} and C Keller",

note = "Funding Information: This work was supported by NIH grants 5R01CA189299,1R01CA143082; the St. Baldrick{\textquoteright}s Foundation; the Braver, Stronger, Smarter Foundation; the Michelle Paternoster Foundation for Sarcoma Research; dancingwithbrad. com; the Christina Renna Foundation; the Friends of Doernbecher Foundation; the Friends of T.J. Foundation; the Clarke Gilles Foundation; and a private anonymous gift in memory of Nanette; Team Naomi Get Well Now. Additional funding was provided to F.G.B. by the Intramural Research Program of the National Cancer Institute. Funding Information: We are grateful to the families who shared the PDX model data. This work was supported by NIH grants 5R01CA189299,1R01CA143082; the St. Baldrick's Foundation; the Braver, Stronger, Smarter Foundation; the Michelle Paternoster Foundation for Sarcoma Research; dancingwithbrad. com; the Christina Renna Foundation; the Friends of Doernbecher Foundation; the Friends of T.J. Foundation; the Clarke Gilles Foundation; and a private anonymous gift in memory of Nanette; Team Naomi Get Well Now. Additional funding was provided to F.G.B. by the Intramural Research Program of the National Cancer Institute. Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = may,

day = "21",

language = "English",

pages = "12",

journal = "Default journal",

publisher = "Current Opinion in Endocrinology Diabetes and Obesity",

}

Bharathy, N, Berlow, N, Wang, E, Abraham, J, Settelmeyer, TP, Hooper, JE, Svalina, MN, Bajwa, Z, Goros, MW, Hernandez, BS, Wolff, JE, Pal, R, Davies, AM, Ashok, A, Bushby, D, Mancini, M, Noakes, C, Goodwin, NC, Ordentlich, P, Keck, J, Hawkins, DS, Rudzinski, ER, Mansoor, A, Perkins, TJ, Vakoc, CR, Michalek, JE & Keller, C 2019, 'Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.', Default journal, pp. 12.

TY - JOUR

T1 - Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

AU - Bharathy, N

AU - Berlow, Noah

AU - Wang, E

AU - Abraham, J

AU - Settelmeyer, T P

AU - Hooper, J E

AU - Svalina, M N

AU - Bajwa, Z

AU - Goros, M W

AU - Hernandez, B S

AU - Wolff, J E

AU - Pal, Ranadip

AU - Davies, A M

AU - Ashok, A

AU - Bushby, D

AU - Mancini, M

AU - Noakes, C

AU - Goodwin, N C

AU - Ordentlich, P

AU - Keck, J

AU - Hawkins, D S

AU - Rudzinski, E R

AU - Mansoor, A

AU - Perkins, T J

AU - Vakoc, C R

AU - Michalek, J E

AU - Keller, C

N1 - Funding Information: This work was supported by NIH grants 5R01CA189299,1R01CA143082; the St. Baldrick’s Foundation; the Braver, Stronger, Smarter Foundation; the Michelle Paternoster Foundation for Sarcoma Research; dancingwithbrad. com; the Christina Renna Foundation; the Friends of Doernbecher Foundation; the Friends of T.J. Foundation; the Clarke Gilles Foundation; and a private anonymous gift in memory of Nanette; Team Naomi Get Well Now. Additional funding was provided to F.G.B. by the Intramural Research Program of the National Cancer Institute. Funding Information: We are grateful to the families who shared the PDX model data. This work was supported by NIH grants 5R01CA189299,1R01CA143082; the St. Baldrick's Foundation; the Braver, Stronger, Smarter Foundation; the Michelle Paternoster Foundation for Sarcoma Research; dancingwithbrad. com; the Christina Renna Foundation; the Friends of Doernbecher Foundation; the Friends of T.J. Foundation; the Clarke Gilles Foundation; and a private anonymous gift in memory of Nanette; Team Naomi Get Well Now. Additional funding was provided to F.G.B. by the Intramural Research Program of the National Cancer Institute. Publisher Copyright: © 2019 The Author(s).

PY - 2019/5/21

Y1 - 2019/5/21

N2 - Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

AB - Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

M3 - Article

SP - 12

JO - Default journal

JF - Default journal

ER -

Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

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