Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Samuel Y. Ng; Noriaki Yoshida; Amanda L. Christie; Mahmoud Ghandi; Neekesh V. Dharia; Joshua Dempster; Mark Murakami; Kay Shigemori; Sara N. Morrow; Alexandria Van Scoyk; Nicolas A. Cordero; Kristen E. Stevenson; Maneka Puligandla; Brian Haas; Christopher Lo; Robin Meyers; Galen Gao; Andrew Cherniack; Abner Louissaint; Valentina Nardi; Aaron R. Thorner; Henry Long; Xintao Qiu; Elizabeth A. Morgan; David M. Dorfman; Danilo Fiore; Julie Jang; Alan L. Epstein; Ahmet Dogan; Yanming Zhang; Steven M. Horwitz; Eric D. Jacobsen; Solimar Santiago; Jian Guo Ren; Vincent Guerlavais; D. Allen Annis; Manuel Aivado; Mansoor N. Saleh; Amitkumar Mehta; Aviad Tsherniak; David Root; Francisca Vazquez; William C. Hahn; Giorgio Inghirami; Jon C. Aster; David M. Weinstock; Raphael Koch

doi:10.1038/s41467-018-04356-9

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Samuel Y. Ng, Noriaki Yoshida, Amanda L. Christie, Mahmoud Ghandi, Neekesh V. Dharia, Joshua Dempster, Mark Murakami, Kay Shigemori, Sara N. Morrow, Alexandria Van Scoyk, Nicolas A. Cordero, Kristen E. Stevenson, Maneka Puligandla, Brian Haas, Christopher Lo, Robin Meyers, Galen Gao, Andrew Cherniack, Abner Louissaint, Valentina NardiAaron R. Thorner, Henry Long, Xintao Qiu, Elizabeth A. Morgan, David M. Dorfman, Danilo Fiore, Julie Jang, Alan L. Epstein, Ahmet Dogan, Yanming Zhang, Steven M. Horwitz, Eric D. Jacobsen, Solimar Santiago, Jian Guo Ren, Vincent Guerlavais, D. Allen Annis, Manuel Aivado, Mansoor N. Saleh, Amitkumar Mehta, Aviad Tsherniak, David Root, Francisca Vazquez, William C. Hahn, Giorgio Inghirami, Jon C. Aster, David M. Weinstock, Raphael Koch

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

76 Citations (Scopus)

Abstract

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Original language	English
Article number	2024
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04356-9
Publication status	Published - 1 Dec 2018
Externally published	Yes

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Ng, S. Y., Yoshida, N., Christie, A. L., Ghandi, M., Dharia, N. V., Dempster, J., Murakami, M., Shigemori, K., Morrow, S. N., Van Scoyk, A., Cordero, N. A., Stevenson, K. E., Puligandla, M., Haas, B., Lo, C., Meyers, R., Gao, G., Cherniack, A., Louissaint, A., ... Koch, R. (2018). Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. Nature Communications, 9(1), Article 2024. https://doi.org/10.1038/s41467-018-04356-9

@article{e0ba41f91fc84a438d4538fcdb0ce9db,

title = "Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models",

abstract = "T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.",

author = "Ng, {Samuel Y.} and Noriaki Yoshida and Christie, {Amanda L.} and Mahmoud Ghandi and Dharia, {Neekesh V.} and Joshua Dempster and Mark Murakami and Kay Shigemori and Morrow, {Sara N.} and {Van Scoyk}, Alexandria and Cordero, {Nicolas A.} and Stevenson, {Kristen E.} and Maneka Puligandla and Brian Haas and Christopher Lo and Robin Meyers and Galen Gao and Andrew Cherniack and Abner Louissaint and Valentina Nardi and Thorner, {Aaron R.} and Henry Long and Xintao Qiu and Morgan, {Elizabeth A.} and Dorfman, {David M.} and Danilo Fiore and Julie Jang and Epstein, {Alan L.} and Ahmet Dogan and Yanming Zhang and Horwitz, {Steven M.} and Jacobsen, {Eric D.} and Solimar Santiago and Ren, {Jian Guo} and Vincent Guerlavais and Annis, {D. Allen} and Manuel Aivado and Saleh, {Mansoor N.} and Amitkumar Mehta and Aviad Tsherniak and David Root and Francisca Vazquez and Hahn, {William C.} and Giorgio Inghirami and Aster, {Jon C.} and Weinstock, {David M.} and Raphael Koch",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04356-9",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

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Ng, SY, Yoshida, N, Christie, AL, Ghandi, M, Dharia, NV, Dempster, J, Murakami, M, Shigemori, K, Morrow, SN, Van Scoyk, A, Cordero, NA, Stevenson, KE, Puligandla, M, Haas, B, Lo, C, Meyers, R, Gao, G, Cherniack, A, Louissaint, A, Nardi, V, Thorner, AR, Long, H, Qiu, X, Morgan, EA, Dorfman, DM, Fiore, D, Jang, J, Epstein, AL, Dogan, A, Zhang, Y, Horwitz, SM, Jacobsen, ED, Santiago, S, Ren, JG, Guerlavais, V, Annis, DA, Aivado, M, Saleh, MN, Mehta, A, Tsherniak, A, Root, D, Vazquez, F, Hahn, WC, Inghirami, G, Aster, JC, Weinstock, DM & Koch, R 2018, 'Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models', Nature Communications, vol. 9, no. 1, 2024. https://doi.org/10.1038/s41467-018-04356-9

TY - JOUR

T1 - Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

AU - Ng, Samuel Y.

AU - Yoshida, Noriaki

AU - Christie, Amanda L.

AU - Ghandi, Mahmoud

AU - Dharia, Neekesh V.

AU - Dempster, Joshua

AU - Murakami, Mark

AU - Shigemori, Kay

AU - Morrow, Sara N.

AU - Van Scoyk, Alexandria

AU - Cordero, Nicolas A.

AU - Stevenson, Kristen E.

AU - Puligandla, Maneka

AU - Haas, Brian

AU - Lo, Christopher

AU - Meyers, Robin

AU - Gao, Galen

AU - Cherniack, Andrew

AU - Louissaint, Abner

AU - Nardi, Valentina

AU - Thorner, Aaron R.

AU - Long, Henry

AU - Qiu, Xintao

AU - Morgan, Elizabeth A.

AU - Dorfman, David M.

AU - Fiore, Danilo

AU - Jang, Julie

AU - Epstein, Alan L.

AU - Dogan, Ahmet

AU - Zhang, Yanming

AU - Horwitz, Steven M.

AU - Jacobsen, Eric D.

AU - Santiago, Solimar

AU - Ren, Jian Guo

AU - Guerlavais, Vincent

AU - Annis, D. Allen

AU - Aivado, Manuel

AU - Saleh, Mansoor N.

AU - Mehta, Amitkumar

AU - Tsherniak, Aviad

AU - Root, David

AU - Vazquez, Francisca

AU - Hahn, William C.

AU - Inghirami, Giorgio

AU - Aster, Jon C.

AU - Weinstock, David M.

AU - Koch, Raphael

PY - 2018/12/1

Y1 - 2018/12/1

N2 - T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

AB - T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

UR - http://www.scopus.com/inward/record.url?scp=85047731447&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-04356-9

DO - 10.1038/s41467-018-04356-9

M3 - Article

C2 - 29789628

AN - SCOPUS:85047731447

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2024

ER -

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

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