Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
by
, ,
Paul Beinhoff
1
,
Lavannya Sabharwal
1,2,3,
Vindhya Udhane
1,2,3,
Cristina Maranto
1,2,3,
Peter S. LaViolette
3,4,
Kenneth M. Jacobsohn
3,5,
Susan Tsai
6,7,
Kenneth A. Iczkowski
1,3,
Liang Wang
3,8,
William A. Hall
3,6,9,
Scott M. Dehm
10,11, 
Deepak Kilari
3,12 and
Marja T. Nevalainen
1,2,3,* 
1
Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2
Department of Pharmacology and Toxicology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3
Prostate Cancer Center of Excellence at the Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
4
Department of Radiology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
5
Department of Urology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
6
Department of Surgery, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
7
Surgical Oncology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
8
Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
9
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
10
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
11
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
12
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(20), 5204; https://doi.org/10.3390/cancers13205204
Submission received: 9 September 2021
/
Revised: 5 October 2021
/
Accepted: 11 October 2021
/
Published: 17 October 2021
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
Simple Summary
Prostate Cancer (PC) is currently estimated to affect 1 in 9 men and is the second leading cause of cancer in men in the US. While androgen deprivation therapy, which targets the androgen receptor, is one of the front-line therapies for advanced PC and for recurrence of organ-confined PC treated with surgery, lethal castrate-resistant PC develops consistently in patients. PC is a multi-focal cancer with different grade carcinoma areas presenting simultaneously. Jak2-Stat5 signaling pathway has emerged as a potentially highly effective molecular target in PCs with positive areas for activated Stat5 protein. Activated Jak2-Stat5 signaling can be readily targeted by the second-generation Jak2-inhibitors that have been developed for myeloproliferative and autoimmune disorders and hematological malignancies. In this review, we analyze and summarize the Jak2 inhibitors that are currently in preclinical and 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.
