Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer

Haddad, Bassem R.; Erickson, Andrew; Udhane, Vindhya; LaViolette, Peter S.; Rone, Janice D.; Kallajoki, Markku; See, William A.; Rannikko, Antti; Mirtti, Tuomas; Nevalainen, Marja T.

doi:10.1158/1055-9965.epi-18-1358

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…PDL1-high-expression was also an independent predictor of time to BCR in multivariate analysis (HR: 3.901; 95% CI: 1.287–11.824; p = 0.016). In a third study, Haddad et al [87] compared the significance of either STAT5 nuclear localization or STAT5 locus amplification, or both, for predicting BCR after RP. The authors showed that positive status for both events was an independent predictor for shorter disease-free survival, by univariate analysis ( p < 0.0001), and for BCR, by multivariate analysis (HR = 2.34; p = 0.014) after RP.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, while the racial or ethnic status of the patient cohort were not defined in these recently published studies, our study is based on a diverse patient cohort, consisting of approximately 70% CA and 30% AA patients. Moreover, in evaluating the predictive value of detecting ERG for BCR, our study we not only used the NanoString platform, but we compared it to IHC and qRT-PCR, whereas only IHC [85, 86] or IHC and FISH [87] were used in the other studies. Lastly, we evaluated a total of 121 genes or gene alteration events for association with progression to BCR while the other studies examined the association of either a single biomarker [85], or two interacting proteins [86], or protein expression and copy number amplification associated with a single gene [87].…”

Section: Discussionmentioning

confidence: 99%

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Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

et al. 2019

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Background: As a major cause of morbidity and mortality among men, prostate cancer is a heterogenous disease, with a vast heterogeneity in the biology of the disease and in clinical outcome. While it often runs an indolent course, local progression or metastasis may eventually develop, even among patients considered “low risk” at diagnosis. Therefore, biomarkers that can discriminate aggressive from indolent disease at an early stage would greatly benefit patients. We hypothesized that tissue specimens from early stage prostate cancers may harbor predictive signatures for disease progression.Methods: We used a cohort of radical prostatectomy patients with longitudinal follow-up, who had tumors with low grade and stage that revealed no signs of future disease progression at surgery. During the follow-up period, some patients either remained indolent (non-BCR) or progressed to biochemical recurrence (BCR). Total RNA was extracted from tumor, and adjacent normal epithelium of formalin-fixed-paraffin-embedded (FFPE) specimens. Differential gene expression in tumors, and in tumor versus normal tissues between BCR and non-BCR patients were analyzed by NanoString using a customized CodeSet of 151 probes.Results: After controlling for false discovery rates, we identified a panel of eight genes (ERG, GGT1, HDAC1, KLK2, MYO6, PLA2G7, BICD1 and CACNAID) that distinguished BCR from non-BCR patients. We found a clear association of ERG expression with non-BCR, which was further corroborated by quantitative RT-PCR and immunohistochemistry assays.Conclusions: Our results identified ERG as the strongest predictor for BCR and showed that potential prognostic prostate cancer biomarkers can be identified from FFPE tumor specimens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

et al. 2019

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“…STAT2 is also associated with poor overall survival in NSCLC [61] . Hyperactivity of STAT5 is associated with enhanced cell viability, tumor growth, and recurrence in prostate cancers [62,63] . In colorectal cancer cell lines, elevated levels of activated STAT6 are correlated with metastasis and decreased apoptosis [64] .…”

Section: Hyperactivation Of Other Statsmentioning

confidence: 99%

Targeting the JAK/STAT pathway in solid tumors

Qureshy¹,

Johnson²,

Grandis³

2020

JCMT

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Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in in vivo models, they also inhibit tumor growth. JAK inhibitors, particularly the JAK1/2 inhibitor ruxolitinib, sensitize cell lines and murine models to chemotherapy, immunotherapy, and oncolytic viral therapy. Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors; two of these inhibitors are already Food and Drug Administration (FDA) approved for the treatment of myeloproliferative disorders and rheumatoid arthritis, making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated. Four JAK inhibitors (two of which are FDA approved for other indications) have exhibited promising anti-cancer effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

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“…Stat5a/b (Stat5) is critical for growth and progression of solid tumors and hematological malignancies, specifically prostate cancer (PC) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and Bcr-Abl-driven leukemias [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. For therapeutic suppression, transcription factors are typically considered suboptimal pharmacological targets because their function relies on protein–protein and protein–DNA interactions that are not easily disrupted by small molecules.…”

Section: Introductionmentioning

confidence: 99%

“…A substantial body of work supports the concept that Stat5 is critical for PC cell viability in vitro and xenograft tumor growth in vivo [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], and IST5 has been shown to induce extensive apoptotic death of PC cells, block growth of PC xenograft tumors in mice in vivo [ 2 , 3 , 4 , 6 , 7 , 8 , 10 , 14 , 15 , 47 ], and induce apoptotic death in patient-derived clinical PCs ex vivo in 3D tumor explant cultures [ 10 , 47 ]. These proof-of-concept data on Stat5 as a therapeutic target protein in PC have been supported by the findings on Stat5 activation in PC predicting early recurrence of the disease and early PC-related death [ 22 , 23 , 25 ]. Stat5 upregulates the hallmarks of the epithelial-to-mesenchymal transition (EMT) that precedes metastasis in PC, and Stat5 promotes DNA repair in PC increasing tolerance of PC to radiation, which is suppressed by IST5 [ 4 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo

Maranto

Udhane

Jia

et al. 2020

Cancers

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Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98–0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders.

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Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer

Cited by 12 publications

References 32 publications

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

Targeting the JAK/STAT pathway in solid tumors

Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo

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