Second-generation jak2 inhibitors for advanced prostate cancer: Are we ready for clinical development?

Paul Beinhoff; Lavannya Sabharwal; Vindhya Udhane; Cristina Maranto; Peter S. Laviolette; Kenneth M. Jacobsohn; Susan Tsai; Kenneth A. Iczkowski; Liang Wang; William A. Hall; Scott M. Dehm; Deepak Kilari; Marja T. Nevalainen

doi:10.3390/cancers13205204

Second-generation jak2 inhibitors for advanced prostate cancer: Are we ready for clinical development?

Paul Beinhoff, Lavannya Sabharwal, Vindhya Udhane, Cristina Maranto, Peter S. Laviolette, Kenneth M. Jacobsohn, Susan Tsai, Kenneth A. Iczkowski, Liang Wang, William A. Hall, Scott M. Dehm, Deepak Kilari, Marja T. Nevalainen

Laboratory Medicine and Pathology

Research output: Contribution to journal › Review article › peer-review

11 Scopus citations

Abstract

Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

Original language	English (US)
Article number	5204
Journal	Cancers
Volume	13
Issue number	20
DOIs	https://doi.org/10.3390/cancers13205204
State	Published - Oct 1 2021

Bibliographical note

Funding Information:
Funding: This work was partially supported by Advancing a Healthier Wisconsin (#5520368) and Wisconsin Cancer Showhouse Grant (#15437) to MTN and a grant from National Institute of Health and the National Cancer Institute (NCI) (1R01CA212097) to LW and MTN, a grant from NCI (R01CA249882) to PSL, a grant National Center for Advancing Translational Sciences, National Institutes of Health (KL2TR001438) to WAH and a grant from AHW (5520566) to PB and MTN.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Anti-androgen resistant prostate cancer
Castrate-resistant prostate cancer (CRPC)
Janus kinase 2 (Jak2)
Prostate cancer (PC)
Signal transducer and activator of transcription (Stat)
Solid tumors

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@article{e87b184476944e65817dba66c8c2e427,

title = "Second-generation jak2 inhibitors for advanced prostate cancer: Are we ready for clinical development?",

abstract = "Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.",

keywords = "Anti-androgen resistant prostate cancer, Castrate-resistant prostate cancer (CRPC), Janus kinase 2 (Jak2), Prostate cancer (PC), Signal transducer and activator of transcription (Stat), Solid tumors",

author = "Paul Beinhoff and Lavannya Sabharwal and Vindhya Udhane and Cristina Maranto and Laviolette, {Peter S.} and Jacobsohn, {Kenneth M.} and Susan Tsai and Iczkowski, {Kenneth A.} and Liang Wang and Hall, {William A.} and Dehm, {Scott M.} and Deepak Kilari and Nevalainen, {Marja T.}",

note = "Funding Information: Funding: This work was partially supported by Advancing a Healthier Wisconsin (#5520368) and Wisconsin Cancer Showhouse Grant (#15437) to MTN and a grant from National Institute of Health and the National Cancer Institute (NCI) (1R01CA212097) to LW and MTN, a grant from NCI (R01CA249882) to PSL, a grant National Center for Advancing Translational Sciences, National Institutes of Health (KL2TR001438) to WAH and a grant from AHW (5520566) to PB and MTN. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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T2 - Are we ready for clinical development?

AU - Beinhoff, Paul

AU - Sabharwal, Lavannya

AU - Udhane, Vindhya

AU - Maranto, Cristina

AU - Laviolette, Peter S.

AU - Jacobsohn, Kenneth M.

AU - Tsai, Susan

AU - Iczkowski, Kenneth A.

AU - Wang, Liang

AU - Hall, William A.

AU - Dehm, Scott M.

AU - Kilari, Deepak

AU - Nevalainen, Marja T.

N1 - Funding Information: Funding: This work was partially supported by Advancing a Healthier Wisconsin (#5520368) and Wisconsin Cancer Showhouse Grant (#15437) to MTN and a grant from National Institute of Health and the National Cancer Institute (NCI) (1R01CA212097) to LW and MTN, a grant from NCI (R01CA249882) to PSL, a grant National Center for Advancing Translational Sciences, National Institutes of Health (KL2TR001438) to WAH and a grant from AHW (5520566) to PB and MTN. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

AB - Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

KW - Anti-androgen resistant prostate cancer

KW - Castrate-resistant prostate cancer (CRPC)

KW - Janus kinase 2 (Jak2)

KW - Prostate cancer (PC)

KW - Signal transducer and activator of transcription (Stat)

KW - Solid tumors

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DO - 10.3390/cancers13205204

M3 - Review article

C2 - 34680353

AN - SCOPUS:85117018634

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 20

M1 - 5204

ER -

Second-generation jak2 inhibitors for advanced prostate cancer: Are we ready for clinical development?

Abstract

Bibliographical note

Keywords

UN SDGs

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