scholarly journals The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2342
Author(s):  
Daniel J. Turnham ◽  
Nicholas Bullock ◽  
Manisha S. Dass ◽  
John N. Staffurth ◽  
Helen B. Pearson
Keyword(s):  
Prostate Cancer ◽  
Precision Medicine ◽  
Cancer Progression ◽  
Improve Patient Care ◽  
Therapeutic Approaches ◽  
Poor Clinical Outcome ◽  
Pten Loss ◽  
Damage Repair ◽  
Phosphatase And Tensin Homologue ◽  
Improve Patient

Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

scholarly journals Abstract LB-230: Oncogenic PKC epsilon and Pten loss converge on activating CXCL13 via atypical NF-κB transcriptional signaling in prostate cancer progression

2017 ◽  
Author(s):  
Rachana Garg ◽  
Jorge Blando ◽  
Carlos Perez ◽  
Martin Abba ◽  
Fernando Benavides ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Pten Loss ◽  
Pkc Epsilon

Therapeutic Approaches Targeting Prostate Cancer Progression Using Novel Voltage-Gated Ion Channel Blockers

2003 ◽  
Vol 2 (3) ◽  
pp. 181-187 ◽  
Author(s):  
Robert A. Sikes ◽  
Alison M. Walls ◽  
W. Nathaniel Brennen ◽  
James D. Anderson ◽  
Indrani Choudhury-Mukherjee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ion Channel ◽  
Cancer Progression ◽  
Channel Blockers ◽  
Prostate Cancer Progression ◽  
Therapeutic Approaches ◽  
Voltage Gated ◽  
Ion Channel Blockers

scholarly journals CDCP1 initiates tumorigenesis and cooperates with PTEN loss to promote senescence evasion and prostate cancer progression

2017 ◽  
Vol 28 ◽  
pp. v1
Author(s):  
A. Alajati ◽  
J. Chen ◽  
A. Alimonti
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Pten Loss

scholarly journals Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias

2021 ◽  
Vol 10 (3) ◽  
pp. 533 ◽  
Author(s):  
Loredana Bury ◽  
Emanuela Falcinelli ◽  
Paolo Gresele
Keyword(s):  
Quality Of Life ◽  
Platelet Count ◽  
Improve Patient Care ◽  
Gene Variants ◽  
Therapeutic Approaches ◽  
Precise Diagnosis ◽  
Hereditary Disorders ◽  
Improve Patient ◽  
Platelet Formation

Inherited thrombocytopenias (IT) are a group of hereditary disorders characterized by a reduced platelet count sometimes associated with abnormal platelet function, which can lead to bleeding but also to syndromic manifestations and predispositions to other disorders. Currently at least 41 disorders caused by mutations in 42 different genes have been described. The pathogenic mechanisms of many forms of IT have been identified as well as the gene variants implicated in megakaryocyte maturation or platelet formation and clearance, while for several of them the pathogenic mechanism is still unknown. A range of therapeutic approaches are now available to improve survival and quality of life of patients with IT; it is thus important to recognize an IT and establish a precise diagnosis. ITs may be difficult to diagnose and an initial accurate clinical evaluation is mandatory. A combination of clinical and traditional laboratory approaches together with advanced sequencing techniques provide the highest rate of diagnostic success. Despite advancement in the diagnosis of IT, around 50% of patients still do not receive a diagnosis, therefore further research in the field of ITs is warranted to further improve patient care.

scholarly journals Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 223
Author(s):  
Hao-Han Chang ◽  
Cheng-Hsueh Lee ◽  
Yei-Tsung Chen ◽  
Chao-Yuan Huang ◽  
Chia-Cheng Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Cancer Susceptibility ◽  
Univariate Analysis ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Mismatch Repair Gene ◽  
Damage Repair

DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63–0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.

Abstract PO-035: Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression

2021 ◽  
Author(s):  
Alexandru Suvac ◽  
Richard Rebello ◽  
Stephen Lyons ◽  
Robert G. Bristow
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Pten Loss

scholarly journals FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis

Oncogene ◽  
2019 ◽  
Vol 38 (26) ◽  
pp. 5265-5280 ◽  
Author(s):  
Parthasarathy Seshacharyulu ◽  
Satyanarayana Rachagani ◽  
Sakthivel Muniyan ◽  
Jawed A. Siddiqui ◽  
Eric Cruz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Small Gtpases ◽  
Prostate Cancer Progression ◽  
Pten Loss

Biomarker analysis of the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 182-182
Author(s):  
Zhen Shi ◽  
Christopher Sweeney ◽  
Sergio Bracarda ◽  
Cora N. Sternberg ◽  
Kim N. Chi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Alterations ◽  
Phase Iii ◽  
Genetic Profile ◽  
Molecular Heterogeneity ◽  
Castration Resistant Prostate Cancer ◽  
Pten Loss ◽  
Castration Resistant ◽  
Damage Repair ◽  
Biomarker Analysis

182 Background: IPATential150 is a randomized trial comparing Ipat + Abi vs placebo + Abi in patients (pts) with 1L mCRPC (NCT03072238). We evaluated the potential associations between PTEN loss, genomic alterations, and country of enrollment (East Asian [EAS] vs non-EAS). Methods: Before randomization, tumor samples (archival > 90%) were centrally tested for PTEN loss by VENTANA PTEN (SP218) immunohistochemistry (IHC) assay (N = 1101). Tumor genetic alterations were profiled by Foundation Medicine FoundationOne CDx (F1CDx) NGS assay (n = 735). Results: Of 1101 pts enrolled, 521 (47%) had PTEN loss by IHC. An overall 76% agreement was observed between PTEN IHC and F1CDx. TMPRSS2 fusion, alterations in TP53 and PTEN were most frequent (28%-32%). Alterations in PIK3CA, SPOP, APC, MYC, RAD21, and genes involved in DNA damage repair, including BRCA2, CDK12, ATM, had a 5%-8% prevalence. PTEN loss (IHC) tended to co-occur with genetic alterations in TP53 and TMPRSS2. The prevalence of PTEN loss in EAS vs non-EAS pts was 35% vs 50% by IHC and 15% vs 31% by F1CDx. Alterations in CDK12, BRCA2, SPOP, and MYC were more prevalent in EAS pts, whereas alterations in TMPRSS2, PTEN, and TP53 were more prevalent in non-EAS pts. Conclusions: This analysis reveals molecular heterogeneity in prostate cancer and association between potentially actionable targets. It also suggests that EAS pts with mCRPC have a genetic profile that may be at least quantitatively different from non-EAS pts. Clinical trial information: NCT03072238. [Table: see text]

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