Browsing by Subject "Prostate cancer"

Now showing 1 - 4 of 4

Open Access
Design of a novel MRI compatible manipulator for image guided prostate interventions
(IEEE, 2005-02) Krieger, A.; Susil, R. C.; Ménard, C.; Coleman, J. A.; Fichtinger, G.; Atalar, Ergin; Whitcomb, L. L.
This paper reports a novel remotely actuated manipulator for access to prostate tissue under magnetic resonance imaging guidance (APT-MRI) device, designed for use in a standard high-field MRI scanner. The device provides three-dimensional MRI guided needle placement with millimeter accuracy under physician control. Procedures enabled by this device include MRI guided needle biopsy, fiducial marker placements, and therapy delivery. Its compact size allows for use in both standard cylindrical and open configuration MRI scanners. Preliminary in vivo canine experiments and first clinical trials are reported.
Open Access
Identification and targeting of deregulated metabolic pathways in metastatic prostate cancer cells
(2023-01) Kaysudu, Irmak
Prostate cancer is the most diagnosed cancer type and the second leading cause of death in men globally. The pathogenesis of prostate cancer mainly relies on the androgen signaling axis. Therefore, androgen deprivation therapy is the primary treatment for prostate cancer. Nevertheless, the disease progression proceeds, followed by castration resistance and androgen independence. Aberrant androgen signaling activity intertwined with the hyperactivated PI3K-Akt signaling pathway has important oncogenic consequences for castration resistance mechanisms. PTEN, a negative regulator of the PI3K/Akt pathway, is one of the most altered tumor suppressor genes in prostate cancer. PTEN loss occurs in the initial stages of prostate cancer and the frequency of its alteration increases in metastatic and castration-resistant prostate cancer. PTEN has both lipid and protein phosphatase activity, with the former antagonizing the PI3K-Akt pathway by converting membrane-associated PIP3 to PIP2. PTEN loss may cause metabolic rewiring in metastatic prostate cancer cells and the associated metabolic vulnerabilities may be tackled for the disease therapy. To understand the impact of PTEN loss in metastatic prostate cancer cells, we created a dox-inducible system in PTEN-null metastatic and castration-naïve LNCaP cells to re-express WT-PTEN and various PTEN functional mutants, and we employed targeted metastatic prostate cancer. Our multidirectional omics studies suggest that the acquisition of resistance to castration depends on the deregulation of the sphingolipid metabolism in metastatic prostate cancer cells. Furthermore, we showed that PTEN re-expression in metastatic and castration-naïve LNCaP cells attenuated sphingosine kinase levels, which might switch the sphingolipid metabolism towards increased sphingomyelin biosynthesis and ceramide phosphorylation. Moreover, we showed decreased PI3K/Akt pathway activity when we inhibited sphingosine kinase with opaganib in LNCaP cells. Our results also showed a significant upregulation in sphingolipid metabolism in castration-resistant C4-2 cells compared to castration-naïve LNCaP. We treated these cells with several sphingolipid metabolism inhibitors and discovered that castration-resistant prostate cancer cells were more sensitive to opaganib or ARN14988, but not to fingolimod, than castration-naïve prostate cancer cells. These findings suggest that sphingolipid metabolism might be a promising target for the treatment of metastatic and castration-resistant prostate cancer. Understanding changes in sphingolipid metabolism may be critical for developing rational combinatorial targeting strategies for prostate cancer in the long run.
Open Access
Mirna based identification of prostate cancer by investigation of urinary exosomes
(2020-08) Bozbeyoğlu, Naz
Prostate cancer is one of the most incident cancer subtypes with high mortality rate. Currently, diagnosis of prostate cancer is based on rectal examination, Prostate Specific Antigen (PSA) testing and biopsy. Normal range of PSA is defined as 0-4 ng/ml and individuals with higher PSA levels are considered as potential prostate cancer patients. However, PSA fluctuates as a result of many factors and it is shown to increase with age. Thus, PSA testing causes significantly high false positive results and many healthy men have biopsy unnecessarily due to high PSA levels or they even get overtreated. This situation has huge psychological as well as financial effects on these people. Herein, we investigated the diagnostic potential of urinary exosomal microRNAs (miRNA) in prostate cancer. Rather than investigation of cellular miRNAs, we focused on exosomal miRNAs because of high integrity of exosomes and their abundance in many biofluids including urine. Development of a sensitive diagnostic method from urine would be advantageous because accurate diagnosis of prostate cancer would be possible by a non-invasive procedure. miRNAs are the small non-coding RNAs and they suppress expression of target genes via degradation of mRNA or post-translational regulation. miRNAs have high potential as cancer biomarkers because they can act as tumor suppressor and repress oncogenic gene expression or function as oncogenic miRNA and suppress tumor suppressor gene expression. For this reason, we identified several candidate exosomal tumor suppressor and oncogenic miRNAs and continued our study with the most potent ones. At the beginning of the study, we validated that we efficiently isolated exosomes via several techniques such as flow cytometry, Dynamic Light Scattering (DLS), Nanoparticle Tracking Analysis (NTA) and Transmission Electron Microscopy (TEM). Then, we studied differential expression of candidate miRNAs in prostate cancer PC-3 cell line. Similar to our literature search findings, we found that expression levels of miR-107, miR-139, miR-145 and miR-204 were significantly lower in PC-3 exosomes in comparison to healthy urinary exosomes. On the other hand, oncomiRs; miR-21-5p, miR-375-5p and miR-574 3p were upregulated in PC-3 cell line exosomes. Of note, expression of another candidate miRNA; miR-30a was almost the same in PC-3 exosomes with healthy controls. We used these results as preliminary data and collected urine specimens from 17 prostate cancer patients. We firstly analyzed their PSA level-age and PSA Level- Gleason Score correlations. Our analyses revealed that PSA level was increasing with age and PSA was not correlated with Gleason Score. We concluded that PSA was being affected by several reasons in addition to tumor formation and it was not correlated with disease progression. Again, this was a finding which supported that a more sensitive diagnosis method than PSA testing was necessary for prostate cancer. When we detected expression levels of candidate miRNAs in urinary exosomes of prostate cancer patients and healthy controls, we observed that miR-107, miR-139, miR-145 and miR-204 were downregulated whereas miR-375-5p was upregulated in patients’ urinary exosomes. For miR-21, there was a very slight upregulation and miR-30a-5p and miR-574-3p levels were almost the same with healthy controls. Further, we wondered the diagnostic potential of these miRNAs in our patient cohort and we performed Receiver Operator Characteristic (ROC) Curve analysis for them. When they were used as combination, our miRNAs had 77% (AUC=0.7731) accuracy in distinguishing patients from healthy controls. After that, we examined miRNA dysregulations in patients with different PSA levels with the hypothesis that they may have different miRNA expression profiles. We saw that expression of miRNAs in exosomes patients with PSA<10 ng/ml and PSA=10-15 ng/ml were very similar with our expectations; downregulation of tumor suppressor and upregulation in oncogenic miRNAs whereas patients with PSA>15 ng/ml had a unique profile and all miRNAs were downregulated. Due to sample size limitations, we only tested diagnostic potential of candidate miRNAs in exosomes of patients with PSA<10 ng/ml and observed that AUC was 0.8500 so we could discriminate patients and healthy controls with 85% accuracy by using our candidate miRNA panel in testing. Taken together, our findings indicated that candidate urinary exosomal tumor suppressor and oncogenic miRNAs which we suggested in thesis are very potent in diagnosis of prostate cancer with differential expressions in prostate cancer patients with different PSA levels and this study opens the way for development of a noninvasive prostate cancer diagnosis method.
Open Access
Targeted metabolomics revealed a key metabolic reprogramming in cholesterol biosynthesis pathway upon PTEN re-expression in PTEN-null, metastatic and castration-resistant prostate cancer
(2022-06) Güngül, Taha Buğra
Prostate cancer is the second most diagnosed type of cancer in males worldwide. Androgen signaling is a main driver of prostate cancers progression and androgen-deprivation therapies (ADT) are remained to be main treatment for preventing progression of the disease. Although ADT is effective at the first line and prolongs overall survival of the patients, eventually disease is recurred, develop resistance to castration and grow in an androgen-independent state, which completely eliminate ADT option. Metastatic and castration-resistant prostate cancers (mCPRC) are the most fatal type of the disease without any effective treatments currently, which is why, molecular drivers that contribute to emergence of castration-resistant phenotype need to be elucidated in order to develop efficient therapeutics against them. Metabolic reprogramming is one of the crucial hallmarks of cancer and loss-of tumor suppressor PTEN is an early and a frequent genetic alteration in prostate cancers, which leads to a hyperactivation of PI3K/Akt/mTOR axis and affects cellular metabolism widely. In this study, we aimed to unveil changes in the metabolome of C4-2 cells which are the type of mCRPC with a PTEN-null genetic background and target metabolic vulnerabilities of these cells. In order to address the question, we employed high-throughput metabolomics assay and revealed changes on metabolome of the cells upon re-expression of PTEN. We found that PTEN re-expression impaired the sphingolipid and cholesterol biosynthesis pathways of C4-2 cells. Upon PTEN re-expression, metabolism of C4-2 cells had tendency to increase the level of anti-survival metabolite; ceramide, and decrease pro-survival metabolite; sphingosine-1-phosphate. In addition to that, PTEN re-expression significantly impaired and downregulated the cholesterol metabolism of these cells. To target these metabolic vulnerabilities, we combined inhibitors of sphingolipid and cholesterol metabolisms with FDA-approved androgen antagonist, MDV3100, to determine possible synergistic effects from the combination of drugs. MDV3100 single treatment had only cytostatic effect on viability of C4-2 cells and combination of simvastatin, cholesterol metabolism inhibitor, with MDV3100 significantly decreased the cellular viability and resulted in significant synergistic effects in inhibiting the growth of C4-2 cells. Thus targeting cholesterol pathway in combination with androgen-deprivation therapies would be a promising approach to develop new combinatorial therapies and combat mCRPC.