scholarly journals Genome-Based Classification and Therapy of Prostate Cancer

Diagnostics ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 62 ◽  
Author(s):  
Arlou Angeles ◽  
Simone Bauer ◽  
Leonie Ratz ◽  
Sabine Klauck ◽  
Holger Sültmann
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Molecular Classification ◽  
Therapy Resistance ◽  
Clinical Practices ◽  
Molecular Alterations ◽  
The Past ◽  
Cancer Genomes ◽  
Treatment Concepts

In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.

scholarly journals Molecular Classification of Prostate Cancer Progression: Foundation for Marker-Driven Treatment of Prostate Cancer

2013 ◽  
Vol 3 (8) ◽  
pp. 849-861 ◽  
Author(s):  
Christopher J. Logothetis ◽  
Gary E. Gallick ◽  
Sankar N. Maity ◽  
Jeri Kim ◽  
Ana Aparicio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Molecular Classification ◽  
Prostate Cancer Progression

scholarly journals NUMB suppression by miR-9-5P enhances CD44+ prostate cancer stem cell growth and metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuan Wang ◽  
Jun Cai ◽  
Lei Zhao ◽  
Dejun Zhang ◽  
Guojie Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Bioinformatics Analysis ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Self Renewal ◽  
Tumor Relapse ◽  
The Past ◽  
Overwhelming Evidence ◽  
Novel Therapeutic Strategies

AbstractExperimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis and luciferase assays and by conducting rescue experiments, we first show that NUMB is directly targeted by microRNA-9-5p (miR-9-5p), an oncogenic miR associated with poor prognosis in many malignancies. We further show that miR-9-5p levels are inversely correlated with NUMB expression in CD44+ PCSCs. miR-9-5p reduced NUMB expression and inhibited numerous PCSC properties including proliferation, migration, invasion as well as self-renewal. Strikingly, overexpression of NUMB in CD44+ PCSCs overcame all of the above PCSC properties enforced by miR-9-5p. Taken together, our results suggest that inhibiting the expression of the oncomiR miR-9-5p and overexpressing NUMB may represent novel therapeutic strategies to target PCSCs and PCa metastasis.

scholarly journals Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kristina Totland Carm ◽  
Andreas M. Hoff ◽  
Anne Cathrine Bakken ◽  
Ulrika Axcrona ◽  
Karol Axcrona ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Classification ◽  
Primary Diagnosis ◽  
The Cancer Genome Atlas ◽  
Clinical Usefulness ◽  
Whole Exome ◽  
Primary Prostate Cancer ◽  
Cancer Genome Atlas ◽  
Prostate Cancers

Abstract Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier’s performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer.

scholarly journals Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 39 ◽  
Author(s):  
Andreas Josefsson ◽  
Karin Larsson ◽  
Eva Freyhult ◽  
Jan-Erik Damber ◽  
Karin Welén
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Progression ◽  
Expression Patterns ◽  
Therapy Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Cancer Specific Survival ◽  
Castration Resistant

Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

scholarly journals Molecular classification of prostate cancer using curated expression signatures

2011 ◽  
Vol 108 (52) ◽  
pp. 21276-21281 ◽  
Author(s):  
E. K. Markert ◽  
H. Mizuno ◽  
A. Vazquez ◽  
A. J. Levine
Keyword(s):  
Prostate Cancer ◽  
Molecular Classification

scholarly journals Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

2009 ◽  
Vol 16 (1) ◽  
pp. 99-111 ◽  
Author(s):  
Emma Samuelson ◽  
Carola Hedberg ◽  
Staffan Nilsson ◽  
Afrouz Behboudi
Keyword(s):  
Cell Biology ◽  
Tumor Model ◽  
Molecular Classification ◽  
Female Rats ◽  
Type I ◽  
Over Expression ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Endometrial Carcinomas

Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (β-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.

scholarly journals The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance

Oncogene ◽  
2021 ◽  
Author(s):  
Ryan Cronin ◽  
Greg N. Brooke ◽  
Filippo Prischi
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Cancer Progression ◽  
Cell Cycle Control ◽  
Therapy Resistance ◽  
Regulation Of Transcription ◽  
S6 Kinase ◽  
Wide Range ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

AbstractProstate cancer (PCa) is the second most commonly occurring cancer in men, with over a million new cases every year worldwide. Tumor growth and disease progression is mainly dependent on the Androgen Receptor (AR), a ligand dependent transcription factor. Standard PCa therapeutic treatments include androgen-deprivation therapy and AR signaling inhibitors. Despite being successful in controlling the disease in the majority of men, the high frequency of disease progression to aggressive and therapy resistant stages (termed castrate resistant prostate cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSK1-4) family is a group of highly conserved Ser/Thr kinases that holds promise as a novel target. RSKs are effector kinases that lay downstream of the Ras/Raf/MEK/ERK signaling pathway, and aberrant activation or expression of RSKs has been reported in several malignancies, including PCa. Despite their structural similarities, RSK isoforms have been shown to perform nonredundant functions and target a wide range of substrates involved in regulation of transcription and translation. In this article we review the roles of the RSKs in proliferation and motility, cell cycle control and therapy resistance in PCa, highlighting the possible interplay between RSKs and AR in mediating disease progression. In addition, we summarize the current advances in RSK inhibitor development and discuss their potential clinical benefits.

scholarly journals Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade

2021 ◽  
Vol 22 (6) ◽  
pp. 2844
Author(s):  
Alena Mickova ◽  
Gvantsa Kharaishvili ◽  
Daniela Kurfurstova ◽  
Mariam Gachechiladze ◽  
Milan Kral ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Slug Expression ◽  
Chemical Inhibition ◽  
Novel Treatment Strategies ◽  
E Cadherin

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.

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