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.

Identification of copper metabolism-related subtypes and establishment of the prognostic model in ovarian cancer

“…We found that LR patients were more sensitive to chemotherapy with Tozasertib, a pan-Aurora inhibitor that exhibited enhanced carboplatin activity in platinum-sensitive and platinum-resistant ovarian cells of different p53 statuses. At low doses, the compound synergized paclitaxel-induced apoptosis and was active against paclitaxel-resistant cells ( 59 ). A phase I trial of 24-hour continuous intravenous volasertib in 27 patients determined that the disease was stabilized in almost half of the patients ( 60 ).…”

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

“…Likewise, currently-available HDAC inhibitors have largely failed in clinical trials, mostly due to their toxicity [68] or lack of efficacy [69, 70]. Conversely, there are a number of ongoing clinical trials for JAK inhibitors – particularly JAK2 inhibitors – in advanced prostate cancer, but thus far these have not demonstrated sufficient monotherapy activity in men with mCRPC ([71]and see NCT00638378; closed due to lack of efficacy). Our data suggest that a number of critical and non-redundant pathways may be involved in enzalutamide resistance and lineage plasticity, suggesting the need for combination trial approaches.…”

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

“…Due to its role in IL-6 mediated signalling, the role of JAK has been explored as a potential therapeutic target to block PCa progression; however, this has proved a challenge. Ruxolitinib is a JAK1/2 inhibitor that reached Phase II trials for metastatic PCa, but the trial was terminated due to low efficiency (Trial identifier: NCT 00638378); however, this should be further investigated in the context of prolonged ADT with antiandrogens [48], where IL-6 signalling is more prevalent [49]. The Jak inhibitor AZD1480 initially also showed promise, suppressing metastasis in pre-clinical models [50]; however, three Phase I trials have been terminated due to unfavourable neurotoxicity profiles [48].…”

“…Ruxolitinib is a JAK1/2 inhibitor that reached Phase II trials for metastatic PCa, but the trial was terminated due to low efficiency (Trial identifier: NCT 00638378); however, this should be further investigated in the context of prolonged ADT with antiandrogens [48], where IL-6 signalling is more prevalent [49]. The Jak inhibitor AZD1480 initially also showed promise, suppressing metastasis in pre-clinical models [50]; however, three Phase I trials have been terminated due to unfavourable neurotoxicity profiles [48]. Another stalling factor in JAK inhibitor development may be a lack of clinically representative cell-based assays [43].…”