Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
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DOI：
10.3390/cancers13205204
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发表时间：
2021-10-17
期刊：
影响因子：
5.2
通讯作者：
Nevalainen MT
中科院分区：
文献类型：
--
作者：
Beinhoff P;Sabharwal L;Udhane V;Maranto C;LaViolette PS;Jacobsohn KM;Tsai S;Iczkowski KA;Wang L;Hall WA;Dehm SM;Kilari D;Nevalainen MT
据估计，前列腺癌（PC）目前影响九分之一的男性，是美国男性癌症的第二大原因。虽然靶向雄激素受体的雄激素剥夺疗法是晚期PC和手术治疗的器官局限性PC复发的一线疗法之一，但患者中持续发生致命的去势抵抗性PC。PC是一种多灶性癌，不同级别的癌区同时出现。Jak 2-Stat 5信号通路已成为具有活化Stat 5蛋白阳性区域的PC中潜在的高效分子靶点。激活的Jak 2-Stat 5信号可以很容易地被第二代Jak 2抑制剂靶向，第二代Jak 2抑制剂已被开发用于骨髓增生性和自身免疫性疾病以及血液恶性肿瘤。本文对目前处于临床前和临床开发阶段的Jak 2抑制剂进行了分析和总结。雄激素剥夺疗法（ADT）治疗转移性和高危前列腺癌（PC）可抑制雄激素受体（AR）驱动的生长途径。随着时间的推移，ADT导致出现致命的去势抵抗性PC（CRPC），这始终是由肿瘤重新激活AR的获得性能力引起的。这导致了更有效地拮抗AR的第二代抗雄激素的开发，如恩杂鲁胺（ENZ）。然而，CRPC对ENZ的耐药性发展迅速。利用PC的临床前模型的研究已经确定，抑制Jak 2-Stat 5信号传导导致广泛的PC细胞凋亡和肿瘤生长减少。在大型临床队列中，Jak 2-Stat 5活性可预测PC进展和复发。最近，Jak 2-Stat 5信号传导被证明在临床前PC模型中诱导耐ENZ的PC生长，进一步强调了Jak 2-Stat 5对于晚期PC的治疗靶向的重要性。骨髓增生性疾病中Jak 2 V617 F体细胞突变的发现引发了针对各种骨髓增生性疾病和自身免疫性疾病以及血液恶性肿瘤的Jak 1/2特异性抑制剂的快速开发。在这里，我们回顾了目前正在开发的针对突变的Jak 2 V617 F与野生型（WT）-Jak 2的Jak 2抑制剂。在这35种具有Jak 2抑制活性的化合物中，那些对WT-Jak 2具有效力的化合物具有很强的先进PC治疗潜力。
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. 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.
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影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
6
作者：
Campbell, CL;Jiang, Z;Savarese, TM
通讯作者：
Savarese, TM
影响因子：
2.7
作者：
Berdeja, J.;Palandri, F.;Gerds, A. T.
通讯作者：
Gerds, A. T.
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
64.5
作者：
Arora VK;Schenkein E;Murali R;Subudhi SK;Wongvipat J;Balbas MD;Shah N;Cai L;Efstathiou E;Logothetis C;Zheng D;Sawyers CL
通讯作者：
Sawyers CL