scholarly journals ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 79
Author(s):  
Conor Hanna ◽  
Victoria L. Dunne ◽  
Steven M. Walker ◽  
Karl T. Butterworth ◽  
Nuala McCabe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cellular Response ◽  
Advanced Prostate Cancer ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Biochemical Failure ◽  
Ionising Radiation ◽  
Effective Treatment Option ◽  
Normal Prostate ◽  
Minimal Toxicity

Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

scholarly journals Combined hormono-radiotherapy in treatment of locally advanced prostate cancer

2009 ◽  
Vol 56 (4) ◽  
pp. 174-181
Author(s):  
Ljiljana Radosevic-Jelic ◽  
V. Stankovic ◽  
T. Josifovski ◽  
M. Dozic ◽  
N. Borojevic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Dose Range ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Complete Regression ◽  
Locally Advanced Prostate Cancer ◽  
Disease Free Interval ◽  
Progression Of Disease

Numerous questions regarding combined hormono-radiotherapy in the treatment of locally advanced prostate cancer still remain open. We present results of combined treatment in 133 our patients with locally advanced prostate cancer. All patients received hormonotherapy as neoadjuvant, concomitant with radiotherapy (tumor dose range 65-72Gy), and adjuvant. In six months follow-up time, complete regression (CR) was noted in 120 patients (90%), partial regression (PR) in 6 (4,5%), stabile disease (SD) in 2 (1,5%) and progression of disease (PD) in 5 patients (4%). In mean follow up time of 17 months (6-77), 13 patients relapsed. Five-year time to progression was 70%. Five-year disease-free interval for CR patients was 70%. At the date of last control CR was noted in 116 patients (87%), PR in 2 patients (2%), SD in 7 patients (5%), and 8 patients (6%) had progressive disease. Second malignancy was noted in 4 patients. Multidisciplinary studies directed towards the optimisation of combined treatment are ongoing. There are no definitive conclusions.

scholarly journals Risk Stratification after Biochemical Failure following Curative Treatment of Locally Advanced Prostate Cancer: Data from the TROG 96.01 Trial

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Allison Steigler ◽  
James W. Denham ◽  
David S. Lamb ◽  
Nigel A. Spry ◽  
David Joseph ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Stratification ◽  
Advanced Prostate Cancer ◽  
Locally Advanced ◽  
Biochemical Failure ◽  
Sensitivity Analyses ◽  
Risk Category ◽  
Locally Advanced Prostate Cancer ◽  
Method Performance ◽  
Cancer Data

Purpose. Survival following biochemical failure is highly variable. Using a randomized trial dataset, we sought to define a risk stratification scheme in men with locally advanced prostate cancer (LAPC).Methods. The TROG 96.01 trial randomized 802 men with LAPC to radiation ± neoadjuvant androgen suppression therapy (AST) between 1996 and 2000. Ten-year follow-up data was used to develop three-tier post-biochemical failure risk stratification schemes based on cutpoints of time to biochemical failure (TTBF) and PSA doubling time (PSADT). Schemes were evaluated in univariable, competing risk models for prostate cancer-specific mortality. The performance was assessed by c-indices and internally validated by the simple bootstrap method. Performance rankings were compared in sensitivity analyses using multivariable models and variations in PSADT calculation.Results. 485 men developed biochemical failure. c-indices ranged between 0.630 and 0.730. The most discriminatory scheme had a high risk category defined by PSADT < 4 months or TTBF < 1 year and low risk category by PSADT > 9 months or TTBF > 3 years.Conclusion. TTBF and PSADT can be combined to define risk stratification schemes after biochemical failure in men with LAPC treated with short-term AST and radiotherapy. External validation, particularly in long-term AST and radiotherapy datasets, is necessary.

Angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 341-341 ◽  
Author(s):  
Nicolae Ghinea
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Vascular Remodeling ◽  
Advanced Prostate Cancer ◽  
Perineural Invasion ◽  
Target Genes ◽  
Locally Advanced ◽  
Locally Advanced Prostate Cancer ◽  
Normal Prostate ◽  
Vasa Nervorum

341 Background: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination encountered in malignancies associated with highly enervated organs. However, the effect of cancer cells on the blood vessels nourishing the nerves (i.e., vasa nervorum) remains unknown. Methods: We used immunohistochemistry involving three specific antibodies that recognize different endothelial markers (CD34, VEGF-R2 and FSHR), and standard histochemical methods (HES, PAS, TRICHROM) to detect changes in the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients diagnosed with locally advanced prostate cancer (LAPC). Genes known to be implicated in the process of angiogenesis and vascular remodeling have been also explored. NanoString nCounter Analysis covering 86 target genes was used for comparison of gene expression levels between LAPC (6 frozen samples) and normal prostate (NP; 2 frozen samples). Results: The percentage of the area occupied by CD34-positive vasa nervorum endothelial cells associated to nerves with PNI was significantly higher than that in nerves without PNI (6.93 ± 1.08 versus 1.76 ± 0.32; p = 0.003), suggesting a process of angiogenesis. In 18/85 (21%) of patients diagnosed with LAPC the vasa nervorum arterioles had a thick (25 ± 5 µm) tunica media consisting of collagen fibers. More than 75% of CD34-positive vasa nervorum of nerves with or without PNI expressed FSHR. In contrast, none of vasa nervorum expressed detectable VEGF-R2. A panel of 19 genes was found to be significantly (p < 0.05), differentially expressed between LAPC and NP. Six of them (ANGPT1, ITGB3, PGGFB, VEGFC, FSHR, and SDC1) have previously been associated with tumor progression, angiogenesis, and metastasis. Other three genes (SELE, SELP, and ESAM) are known to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. Conclusions: Perineural invasion of cancer cells caused angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.

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