Dataset Information

PI-3 kinase p110?: a therapeutic target in advanced prostate cancers.

ABSTRACT: Prostate cancers in the castration-resistant stage are life-threatening because they are not curable in clinic. The novel androgen receptor inhibitor Xandi (Enzalutamide) and the new CYP17 inhibitor Zytiga (Abiraterone) prolonged patient survival only a few months in advanced prostate cancers. Therefore, novel therapeutic agents for advanced prostate cancers are urgently needed. PI-3 kinases are major intracellular signaling molecules that regulate multiple signal pathways related to cellular metabolism, cytokinesis, growth and survival. Accumulating evidence in the literature indicates that some isoforms of this kinase family are oncogenic and abnormally expressed in various human cancers, including prostate cancers. Recent extensive studies from our group and others showed that PI-3 kinase p110? is aberrantly overexpressed in advanced prostate cancers and is critical for prostate cancer development and progression as demonstrated in cell-based and animal models. Importantly, novel p110?-specific inhibitors have been developed and are currently been testing in clinical trials. In this article, we will briefly summarize recent developments in this regard.

SUBMITTER: Li B

PROVIDER: S-EPMC4219313 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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PI-3 kinase p110β: a therapeutic target in advanced prostate cancers.

Li Benyi B Sun Aijing A Jiang Wencong W Thrasher J Brantley JB Terranova Paul P

American journal of clinical and experimental urology 20141002 3

Prostate cancers in the castration-resistant stage are life-threatening because they are not curable in clinic. The novel androgen receptor inhibitor Xandi (Enzalutamide) and the new CYP17 inhibitor Zytiga (Abiraterone) prolonged patient survival only a few months in advanced prostate cancers. Therefore, novel therapeutic agents for advanced prostate cancers are urgently needed. PI-3 kinases are major intracellular signaling molecules that regulate multiple signal pathways related to cellular me ...[more]

PMID: 25374921

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Project description:BackgroundCD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated.ObjectiveTo characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes.Design, setting, and participantsRNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38+ TIIC densities between CSPC and CRPC biopsies were analysed using a negative binomial mixed model. Differences in the proportions of CD38+ epithelial cells between non-matched benign prostatic epithelium and PC were compared using Fisher's exact test. Differences in the proportions of biopsies containing CD38+ tumour epithelial cells between matched CSPC and CRPC biopsies were compared by McNemar's test. Univariable and multivariable survival analyses were performed using Cox regression models.Results and limitationsCD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38+ TIIC density increased with progression to CRPC and was independently associated with worse overall survival. Future studies are required to dissect TIIC CD38 function.ConclusionsCD38+ prostate TIICs associate with worse survival and immunosuppressive mechanisms. The role of CD38 in PC progression warrants investigation as insights into its functions may provide rationale for CD38 targeting in lethal PC.Patient summaryCD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier.

Dataset Information

PI-3 kinase p110?: a therapeutic target in advanced prostate cancers.

Publications

PI-3 kinase p110β: a therapeutic target in advanced prostate cancers.

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