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Prostatic Neoplasms: HELP
Articles from Kentucky
Based on 163 articles published since 2010
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These are the 163 published articles about Prostatic Neoplasms that originated from Kentucky during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Editorial Low-Fat Abiraterone Food Effect Is of Little Consequence. 2018

Kolesar, Jill M / Liu, Glenn X. ·Jill M. Kolesar, University of Kentucky, Lexington, KY · and Glenn X. Liu, University of Wisconsin-Madison, Madison, WI. ·J Clin Oncol · Pubmed #29590006.

ABSTRACT: -- No abstract --

2 Editorial Nuclear spindles pave the way to metastasis. 2018

Hensley, Patrick J / Kyprianou, Natasha. ·Department of Urology, University of Kentucky, Lexington, KY, USA; Department of Molecular Biochemistry, University of Kentucky, Lexington, KY, USA; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. ·Oncotarget · Pubmed #29560085.

ABSTRACT: -- No abstract --

3 Review Apalutamide: A new agent in the management of prostate cancer. 2019

May, Megan B / Glode, Ashley E. ·Department of Pharmacy, Baptist Health Lexington, Lexington, KY, USA. · Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Boulder, CO, USA. ·J Oncol Pharm Pract · Pubmed #31359832.

ABSTRACT: Apalutamide is a competitive inhibitor of the androgen receptor and binds directly to the ligand-binding domain. The US Food and Drug Administration approved apalutamide on 14 February 2018 for use in patients with nonmetastatic castration-resistant prostate cancer based upon results from the phase III SPARTAN trial demonstrating significantly longer metastasis-free survival over placebo. The SPARTAN trial evaluated 1207 patients with nonmetastatic castration-resistant prostate cancer who were randomized 2:1 to apalutamide or placebo in combination with androgen deprivation therapy. Patients who received apalutamide experienced statistically significantly longer metastasis-free survival (40.5 versus 16.2 months, hazard ratio 0.28 (95% confidence interval = 0.23-0.35); P < 0.0001), which was the major efficacy outcome. Rash, hypothyroidism, and fracture were reported to occur more frequently with apalutamide than placebo. Based upon these results, apalutamide was deemed a safe and effective treatment option for patients with nonmetastatic castration-resistant prostate cancer. Clinical trials are ongoing to expand its indication in the metastatic setting, and identify additional roles for apalutamide in the management of prostate cancer such as in the castrate-sensitive metastatic setting.

4 Review Impact of α-adrenoceptor antagonists on prostate cancer development, progression and prevention. 2019

Wade, Cameron A / Goodwin, Jeffrey / Preston, David / Kyprianou, Natasha. ·Department of Urology, University of Kentucky College of Medicine Lexington, Kentucky 40536, USA. · Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine Lexington, Kentucky 40536, USA. · Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine Lexington, Kentucky 40536, USA. ·Am J Clin Exp Urol · Pubmed #30906804.

ABSTRACT: Two decades following the discovery that α1-adrenoceptor antagonists suppress prostate tumor growth at the molecular and cellular level, the impact of α-blockade as re-purposed treatment strategy in the medical management of prostate cancer is gradually being recognized. Prostate cancer is the second most common cause of cancer deaths among males in the United States, yet the disease maintains inconsistent recommendations for prevention and screening. The functional relationship between α-adrenergic signaling and smooth muscle cells in the stroma of the prostate gland and the bladder neck empowered the use of α-adrenoceptor antagonists for the relief of urethral obstruction and clinical symptoms associated with benign prostatic hyperplasia (BPH). Adrenoceptors are G-protein-coupled receptors (GCPRs) that are functionally bound by catecholamines: epinephrine (ER) and norepinephrine (NE). The α1A adrenoceptor subtype is primarily responsible for smooth muscle contraction in the bladder neck and prostate gland. α1-adrenoceptor antagonists are clinically indicated as first-line therapies for the relief of BPH, hypertension, and post-traumatic stress disorder (PTSD). Compelling evidence from cellular and pre-clinical models have identified additional effects of α1-adrenoceptor antagonists regarding their ability to induce apoptosis-mediated suppression of prostate tumor growth and metastasis. Additionally, early epidemiologic data suggest that they may serve as a safe treatment to reduce the risk of prostate cancer. Optimization of quinazoline based compounds (doxazosin) to exploit pharmacologic targeting of tumor growth and vascularization revealed high efficacy of the lead novel compound DZ-50 against prostate tumors. This review discusses the experimental and pre-clinical evidence on the impact of α-blockade on prostate cancer.

5 Review Prostate tumor neuroendocrine differentiation via EMT: The road less traveled. 2019

Dicken, Haley / Hensley, Patrick J / Kyprianou, Natasha. ·Department of Urology, University of Kentucky College of Medicine, Lexington, KY, USA. · Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA. · Department of Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA. ·Asian J Urol · Pubmed #30775251.

ABSTRACT: The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease. Aberrant transforming-growth factor-β (TGF-β) signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition (EMT), and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer (CRPC). Neuroendocrine prostate cancer (NEPC) is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics. The androgen receptor (AR) is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC. The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions, and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive, acquire the neuroendocrine phenotype, and rapidly metastasize. Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients, but therapeutic resistance invariability develops, leading to mortality. Compelling evidence from our group recently demonstrated that chemotherapy (cabazitaxel, second line taxane chemotherapy), or TGF-β receptor signaling targeted therapy, caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation, in

6 Review Profiles of Radioresistance Mechanisms in Prostate Cancer. 2018

Chaiswing, Luksana / Weiss, Heidi L / Jayswal, Rani D / Clair, Daret K St / Kyprianou, Natasha. ·Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. · The Markey Biostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, Lexington, Kentucky. · Department of Toxicology and Cancer Biology, Department of Urology, Department of Biochemistry, University of Kentucky, Lexington, Kentucky. ·Crit Rev Oncog · Pubmed #29953367.

ABSTRACT: Radiation therapy (RT) is commonly used for the treatment of localized prostate cancer (PCa). However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently causing metastasis and cancer recurrence. Understanding the molecular events that cause radioresistance in PCa will enable us to develop adjuvant treatments for enhancing the efficacy of RT. Radioresistant PCa depends on the elevated DNA repair system and the intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and scavenge anti-cancer regimens, whereas the elevated heat shock protein 90 (HSP90) and the epithelial-mesenchymal transition (EMT) enable radioresistant PCa cells to metastasize after exposure to radiation. The up-regulation of the DNA repairing system, ROS, HSP90, and EMT effectors has been studied extensively, but not targeted by adjuvant therapy of radioresistant PCa. Here, we emphasize the effects of ionizing radiation and the mechanisms driving the emergence of radioresistant PCa. We also address the markers of radioresistance, the gene signatures for the predictive response to radiotherapy, and novel therapeutic platforms for targeting radioresistant PCa. This review provides significant insights into enhancing the current knowledge and the understanding toward optimization of these markers for the treatment of radioresistant PCa.

7 Review Personalization of prostate cancer therapy through phosphoproteomics. 2018

Yang, Wei / Freeman, Michael R / Kyprianou, Natasha. ·Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Departments of Urology, Molecular and Cellular Biochemistry, Pathology and Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA. nkypr2@email.uky.edu. ·Nat Rev Urol · Pubmed #29752463.

ABSTRACT: Castration-resistant prostate cancer (CRPC) remains incurable despite the approval of several new treatments. Identification of new biomarkers and therapeutic targets to enable personalization of CRPC therapy, with the aim of maximizing therapeutic responses and minimizing toxicity in patients, is urgently needed. Prostate cancer progression and therapeutic resistance are frequently driven by aberrantly activated kinase signalling pathways that are amenable to pharmacological inhibition. Personalized phosphoproteomics, which enables the analysis of signalling networks in individual tumours, is a promising approach to advance personalized therapy by discovering biomarkers of pathway activity and clinically actionable targets. Several technologies for global and targeted phosphoproteomic analysis exist, each with its own strengths and shortcomings. Global discovery phosphoproteomics is predominantly conducted using liquid chromatography-tandem mass spectrometry coupled with data-dependent or data-independent acquisition technologies. Multiplexed targeted phosphoproteomics can be divided into platforms based on mass spectrometry or antibodies, including selected or parallel reaction monitoring and triggered by offset, multiplexed, accurate mass, high-resolution, absolute quantification (known as TOMAHAQ) or forward-phase or reverse-phase protein arrays, respectively. Several obstacles still need to be overcome before the full potential of phosphoproteomics can be realized in routine clinical practice, but a future phosphoproteomics-centric trans-omic profiling approach should enable optimized personalized CRPC management through improved biomarkers and targeted treatments.

8 Review Profiling Prostate Cancer Therapeutic Resistance. 2018

Wade, Cameron A / Kyprianou, Natasha. ·Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA. cameron.wade@uky.edu. · Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA. nkypr2@uky.edu. · Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA. nkypr2@uky.edu. · Department of Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA. nkypr2@uky.edu. ·Int J Mol Sci · Pubmed #29562686.

ABSTRACT: The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.

9 Review Cell death under epithelial-mesenchymal transition control in prostate cancer therapeutic response. 2018

Begemann, Diane / Anastos, Harry / Kyprianou, Natasha. ·Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, USA. · Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky, USA. · Department of Molecular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA. ·Int J Urol · Pubmed #29345000.

ABSTRACT: Prostate cancer is a widespread problem among men, with >160 000 new cases in 2017 alone. Androgen deprivation therapy is commonly used in prostate cancer treatment to block androgens required for cancer growth, but disease relapse after androgen deprivation therapy is both common and severe. Changes in androgen receptor signaling from androgen deprivation therapy have been linked to therapeutic resistance and tumor progression. Resistant cells can become reprogrammed to undergo epithelial-mesenchymal transition, a phenotypic switch from benign, epithelial cells to a mobile cell with mesenchymal traits. In these cells, attachment to their epithelial cell layer is no longer required for survival. Anoikis is a form of cell death that occurs when detachment from other cells and the basement membrane occurs. Epithelial cells have been shown to undergo epithelial-mesenchymal transition, avoid anoikis induction and progress to a metastatic phenotype. In prostate cancer progression to advanced disease, epithelial-mesenchymal transition induction (characterized by loss of epithelial cellular attachment protein E-cadherin) correlates with a higher Gleason score, tumor progression, increased metastasis and higher biochemical recurrence. The concept of interfacing epithelial-mesenchymal transition with anoikis in the tumor microenvironment landscape will be discussed here, with focus on the significance of the functional exchange between the two processes in therapeutic targeting of advanced disease. The current evidence on the impact of loss of cell-cell contact, acquisition of chemoresistance, immune escape and metastatic spread in advanced tumors in response to transforming growth factor-β on prostate cancer metastasis will be also discussed. The signaling cross-talk between transforming growth factor-β and androgen receptor signaling will be interrogated as a new therapeutic platform for the development of combination strategies to impair prostate cancer metastasis.

10 Review Prostate Cancer Biomarkers: Current Status. 2017

Hodges, Kurt B / Bachert, Emily / Cheng, Liang. ·Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, Kentucky. · Departments of Pathology, Indiana University School of Medicine, Indianapolis, USA; Department of Urology, Indiana University School of Medicine, Indianapolis, USA. ·Crit Rev Oncog · Pubmed #29604917.

ABSTRACT: Prostate cancer (PCa) is the second most frequently diagnosed cancer among men worldwide. Given the biological heterogeneity in localized PCa and its variable clinical course, a personalized approach to patient risk stratification and management is needed. A variety of high-throughput technologies, such as next-generation sequencing, transcriptomic, epigenetic, and metabolomic modalities have led to an improved understanding of the genomic basis of PCa and the identification of PCa biomarkers. Novel genomic approaches offer additional information to improve clinical decision making. The goal of this report is to review the use of currently available molecular biomarkers in the diagnosis and prognostication of PCa outcome.

11 Review miRNAs associated with prostate cancer risk and progression. 2017

Luu, Hung N / Lin, Hui-Yi / Sørensen, Karina Dalsgaard / Ogunwobi, Olorunseun O / Kumar, Nagi / Chornokur, Ganna / Phelan, Catherine / Jones, Dominique / Kidd, LaCreis / Batra, Jyotsna / Yamoah, Kosj / Berglund, Anders / Rounbehler, Robert J / Yang, Mihi / Lee, Sang Haak / Kang, Nahyeon / Kim, Seung Joon / Park, Jong Y / Di Pietro, Giuliano. ·Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. · Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL, USA. · Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. · Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. · Department of Biological Sciences, Hunter College of The City University of New York, New York, NY, 10065, USA. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Department of Pharmacology and Toxicology, James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA. · Australian Prostate Cancer Research Centre-QLD, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Australia. · Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Research Center for Cell Fate Control, College of Pharmacy, Sookmyoung Women's University, Seoul, Republic of Korea. · Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. Jong.Park@moffitt.org. · Department of Pharmacy, Federal University of Sergipe, Rodovia Marechal Rodon, Jardim Rosa Elze, Sao Cristóvão, Brazil. ·BMC Urol · Pubmed #28320379.

ABSTRACT: Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, -21, 106b, 141, -145, -205, -221, and -375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers.

12 Review Mechanisms of Therapeutic Resistance in Prostate Cancer. 2017

Nakazawa, Mary / Paller, Channing / Kyprianou, Natasha. ·Departments of Urology, Molecular and Cellular Biochemistry, Pathology and Toxicology and Cancer Biology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY, 40536, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. · Departments of Urology, Molecular and Cellular Biochemistry, Pathology and Toxicology and Cancer Biology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY, 40536, USA. nkypr2@email.uky.edu. ·Curr Oncol Rep · Pubmed #28229393.

ABSTRACT: Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

13 Review Epithelial-mesenchymal-transition regulators in prostate cancer: Androgens and beyond. 2017

Nakazawa, Mary / Kyprianou, Natasha. ·Departments of Urology, Biochemistry, Pathology and Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, United States, United States. · Departments of Urology, Biochemistry, Pathology and Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, United States, United States. Electronic address: nkypr2@uky.edu. ·J Steroid Biochem Mol Biol · Pubmed #27189666.

ABSTRACT: Castration resistant prostate cancer (CRPC) remains one of the leading causes of cancer deaths among men. Conventional therapies targeting androgen signaling driven tumor growth have provided limited survival benefit in patients. Recent identification of the critical molecular and cellular events surrounding tumor progression, invasion, and metastasis to the bone as well as other sites provide new insights in targeting advanced disease. Epithelial mesenchymal transition (EMT) is a process via which epithelial cells undergo morphological changes to a motile mesenchymal phenotype, a phenomenon implicated in cancer metastasis but also therapeutic resistance. Therapeutic targeting of EMT has the potential to open a new avenue in the treatment paradigm of CRPC through the reversion of the invasive mesenchymal phenotype to the well differentiated tumor epithelial tumor phenotype. Overcoming therapeutic resistance in metastatic prostate cancer is an unmet need in today's clinical management of advanced disease. This review outlines our current understanding of the contribution of EMT and its reversal to MET in prostate cancer progression and therapeutic resistance, and the impact of selected targeting of mechanisms of resistance via EMT towards a therapeutic benefit in patients with CRPC.

14 Review Inflammation in prostate cancer progression and therapeutic targeting. 2015

Stark, Timothy / Livas, Lydia / Kyprianou, Natasha. ·1 Department of Urology, 2 Department of Molecular Biochemistry, 3 Department of Pathology, 4 The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA. ·Transl Androl Urol · Pubmed #26816843.

ABSTRACT: Chronic inflammation contributes to the onset and progression of human cancer, via modifications in the tumor microenvironment by remodeling the extracellular matrix (ECM) and initiating epithelial mesenchymal transition (EMT). At the biological level, chronically inflamed cells release cytokines that are functionally dictating a constitutively active stroma, promoting tumor growth and metastasis. In prostate cancer, inflammation correlates with increased development of "risk factor" lesions or proliferative inflammatory atrophy (PIA). Chronic inflammation in benign prostate biopsy specimens can be associated with high-grade prostate tumors in adjacent areas. In this article, we discuss the current understanding of the incidence of inflammation in prostate cancer progression and the significance of the process in therapeutic targeting of specific inflammatory signaling pathways and critical effectors during tumor progression. Further understanding of the process of chronic inflammation in prostate tumor progression to metastasis will enable development and optimization of novel therapeutic modalities for the treatment of high-risk patients with advanced disease.

15 Review Epithelial-mesenchymal transition in prostatic disease. 2015

Broster, Seth A / Kyprianou, Natasha. ·Departments of Urology, Molecular Biochemistry, Pathology, Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA. ·Future Oncol · Pubmed #26551285.

ABSTRACT: A fully differentiated epithelium of the normal prostate gland allows epithelial cells to de-differentiate into mesenchymal-like derivatives via the process of epithelial-mesenchymal transition (EMT) and redifferentiate via the reverse process, mesenchymal-epithelial transition. This review discusses the phenotypic changes associated with EMT and its programming in the development of the two growth disorders of the aging prostate gland, benign prostatic hyperplasia and prostate adenocarcinoma. Considering the cellular heterogeneity that characterizes both conditions, identifying the transcriptional programming of the phenotypic framework defining EMT and its reverse process mesenchymal-epithelial transition in their pathological landscape will enable novel platforms for biomarker-driven therapeutics and their implementation in benign prostatic hyperplasia and prostate cancer.

16 Review Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer. 2015

Martin, Sarah K / Kyprianou, Natasha. ·Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA. · Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Pathology and Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA. Electronic address: nkypr2@email.uky.edu. ·Adv Cancer Res · Pubmed #26093899.

ABSTRACT: Prostate cancer is a tumor addicted to androgen receptor (AR) signaling, even in its castration resistant state, and recently developed antiandrogen therapies including Abiraterone acetate and enzalutamide effectively target the androgen signaling axis, but there is ultimately recurrence to lethal disease. Development of advanced castration-resistant prostate cancer (CRPC) is a biological consequence of lack of an apoptotic response of prostate tumor cells to androgen ablation. Taxanes represent the major clinically relevant chemotherapy for the treatment of patients with metastatic CRPC; unfortunately, they do not deliver a cure but an extension of overall survival. First-generation taxane chemotherapies, Docetaxel (Taxotere), effectively target the cytoskeleton by stabilizing the interaction of β-tubulin subunits of microtubules preventing depolymerization, inducing G2M arrest and apoptosis. Shifting the current paradigm is a growing evidence to indicate that Docetaxel can effectively target the AR signaling axis by blocking its nuclear translocation and transcriptional activity in androgen-sensitive and castration-resistant prostate cancer cells, implicating a new mechanism of cross-resistance between microtubule-targeting chemotherapy and antiandrogen therapies. More recently, Cabazitaxel has emerged as a second-line taxane chemotherapy capable of conferring additional survival benefit to patients with CRPC previously treated with Docetaxel or in combination with antiandrogens. Similar to Docetaxel, Cabazitaxel induces apoptosis and G2M arrest; in contrast to Docetaxel, it sustains AR nuclear accumulation although it reduces the overall AR levels and FOXO1 expression. Cabazitaxel treatment also leads to downregulation of the microtubule-depolymerizing mitotic kinesins, MCAK, and HSET, preventing their ability to depolymerize microtubules and thus enhancing sensitivity to taxane treatment. The molecular mechanisms underlying taxane resistance involve mutational alterations in the tubulin subunits, microtubule dynamics, phenotyping programming of the epithelial-to-mesenchymal transition landscape, and the status of AR activity. This chapter discusses the mechanisms driving the therapeutic resistance of taxanes and antiandrogen therapies in CRPC, and the role of AR in potential interventions toward overcoming such resistance in patients with advanced metastatic disease.

17 Review Models and methods for analyzing DCE-MRI: a review. 2014

Khalifa, Fahmi / Soliman, Ahmed / El-Baz, Ayman / Abou El-Ghar, Mohamed / El-Diasty, Tarek / Gimel'farb, Georgy / Ouseph, Rosemary / Dwyer, Amy C. ·BioImaging Laboratory, Department of Bioengineering, University of Louisville, Louisville, Kentucky 40292 and Electronics and Communication Engineering Department, Mansoura University, Mansoura 35516, Egypt. · BioImaging Laboratory, Department of Bioengineering, University of Louisville, Louisville, Kentucky 40292. · Radiology Department, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt. · Department of Computer Science, University of Auckland, Auckland 1142, New Zealand. · Kidney Transplantation-Kidney Disease Center, University of Louisville, Louisville, Kentucky 40202. ·Med Phys · Pubmed #25471985.

ABSTRACT: PURPOSE: To present a review of most commonly used techniques to analyze dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), discusses their strengths and weaknesses, and outlines recent clinical applications of findings from these approaches. METHODS: DCE-MRI allows for noninvasive quantitative analysis of contrast agent (CA) transient in soft tissues. Thus, it is an important and well-established tool to reveal microvasculature and perfusion in various clinical applications. In the last three decades, a host of nonparametric and parametric models and methods have been developed in order to quantify the CA's perfusion into tissue and estimate perfusion-related parameters (indexes) from signal- or concentration-time curves. These indexes are widely used in various clinical applications for the detection, characterization, and therapy monitoring of different diseases. RESULTS: Promising theoretical findings and experimental results for the reviewed models and techniques in a variety of clinical applications suggest that DCE-MRI is a clinically relevant imaging modality, which can be used for early diagnosis of different diseases, such as breast and prostate cancer, renal rejection, and liver tumors. CONCLUSIONS: Both nonparametric and parametric approaches for DCE-MRI analysis possess the ability to quantify tissue perfusion.

18 Review Cytoskeleton targeting value in prostate cancer treatment. 2014

Martin, Sarah K / Kamelgarn, Marisa / Kyprianou, Natasha. ·Departments of Molecular and Cellular Biochemistry and Urology and The Markey Cancer Center, University of Kentucky College of Medicine Lexington, KY, USA. ·Am J Clin Exp Urol · Pubmed #25374905.

ABSTRACT: Prostate cancer is a disease that affects hundreds of thousands of men in the United States each year. In the early stages of advanced prostate cancer, the disease can be suppressed by androgen deprivation therapy (ADT). Eventually, however, most patients experience resistance to androgen deprivation, and their treatment transitions to alternative targeting of the androgen axis with abiraterone and enzalutamide, as well as taxane-based chemotherapy. Development of advanced castration-resistant prostate cancer (CRPC) is a consequence of lack of an apoptotic response by the tumor cells to treatment. Understanding the mechanisms contributing to prostate tumor therapeutic resistance and progression to metastasis requires dissection of the signaling mechanisms navigating tumor invasion and metastasis as mediated by cell-matrix interactions engaging components of the extracellular matrix (ECM), to form adhesion complexes. For a tumor call to metastasize from the primary tumor, it requires disruption of cell-cell interactions from the surrounding cells, as well as detachment from the ECM and resistance to anoikis (apoptosis upon cell detachment from ECM). Attachment, movement and invasion of cancer cells are functionally facilitated by the actin cytoskeleton and tubulin as the structural component of microtubules. Transforming growth factor (TGF)-β has tumor-inhibitory activity in the early stages of tumorigenesis, but it promotes tumor invasive characteristics in metastatic disease. Recent evidence implicates active (dephosphorylated) cofilin, an F-actin severing protein required for cytoskeleton reorganization, as an important contributor to switching TGF-β characteristics from a growth suppressor to a promoter of prostate cancer invasion and metastasis. Cancer cells eventually lose the ability to adhere to adjacent neighboring cells as well as ECM proteins, and via epithelial-mesenchymal transition (EMT), acquire invasive and metastatic characteristics. Microtubule-targeting chemotherapeutic agents, taxanes, are used in combination with antiandrogen strategies to increase the survival rate in patients with CRPC. This review addresses the development of therapeutic platform for targeting the integrity of actin cytoskeleton to impair prostate cancer progression.

19 Review Redox-mediated and ionizing-radiation-induced inflammatory mediators in prostate cancer development and treatment. 2014

Miao, Lu / Holley, Aaron K / Zhao, Yanming / St Clair, William H / St Clair, Daret K. ·1 Graduate Center for Toxicology, University of Kentucky , Lexington, Kentucky. ·Antioxid Redox Signal · Pubmed #24093432.

ABSTRACT: SIGNIFICANCE: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. RECENT ADVANCES: Ionizing radiation (IR)-generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. CRITICAL ISSUES: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. FUTURE DIRECTIONS: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues.

20 Review Therapeutic value of quinazoline-based compounds in prostate cancer. 2013

Bilbro, Johnathan / Mart, Matthew / Kyprianou, Natasha. ·Combs Res. Bldg., Rm. 306, University of Kentucky Medical Center, Lexington, KY 40536, U.S.A. nkypr2@uky.edu. ·Anticancer Res · Pubmed #24222103.

ABSTRACT: Certain α1-adrenoreceptor antagonists induce significant apoptosis and impair tumor vascularity without affecting cellular proliferation, effects specific to the quinazoline structure. These anticancer effects have been attributed to both induction of classical apoptosis and reversal of anoikis resistance via disruption of integrin-mediated cell survival pathways. Recent drug optimization efforts have generated several novel compounds with quinazoline-derived chemical structure that exert potent anti-tumor activity via anoikis. Results from pre-clinical and clinical studies implicate a potential value of quinazoline-based analogues in prostate cancer prevention and therapy. A retrospective study of a large patient cohort at our center, revealed that treatment with α1-andrenoreceptor antagonists significantly reduced the risk of developing prostate cancer, indicating a potential chemopreventative mechanism for these FDA-approved agents. In the present review we discuss the current understanding of the signaling mechanisms reversing anoikis resistance by the quinazoline-based compounds in prostate tumors, towards enabling identification of novel therapeutic targets for the treatment of metastatic castration-resistant prostate cancer (CRPC).

21 Review Role of inflammasomes and their regulators in prostate cancer initiation, progression and metastasis. 2013

Veeranki, Sudhakar. ·Department of Biochemistry and Molecular Biology, University of Louisville, Baxter II, Rm. 117, 580 S. Preston St., Louisville, KY 40202, USA. veeransr@gmail.com ·Cell Mol Biol Lett · Pubmed #23793845.

ABSTRACT: Prostate cancer is one of the main cancers that affect men, especially older men. Though there has been considerable progress in understanding the progression of prostate cancer, the drivers of its development need to be studied more comprehensively. The emergence of resistant forms has also increased the clinical challenges involved in the treatment of prostate cancer. Recent evidence has suggested that inflammation might play an important role at various stages of cancer development. This review focuses on inflammasome research that is relevant to prostate cancer and indicates future avenues of study into its effective prevention and treatment through inflammasome regulation. With regard to prostate cancer, such research is still in its early stages. Further study is certainly necessary to gain a broader understanding of prostate cancer development and to create successful therapy solutions.

22 Review Targeting caspases in cancer therapeutics. 2013

Hensley, Patrick / Mishra, Murli / Kyprianou, Natasha. ·Department of Urology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA. ·Biol Chem · Pubmed #23509217.

ABSTRACT: The identification of the fundamental role of apoptosis in the growth balance and normal homeostasis against cell proliferation led to the recognition of its loss contributing to tumorigenesis. The mechanistic significance of reinstating apoptosis signaling towards selective targeting of malignant cells heavily exploits the caspase family of death-inducing molecules as a powerful therapeutic platform for the development of potent anticancer strategies. Some apoptosis inhibitors induce caspase expression and activity in preclinical models and clinical trials by targeting both the intrinsic and extrinsic apoptotic pathways and restoring the apoptotic capacity in human tumors. Furthermore, up-regulation of caspases emerges as a sensitizing mechanism for tumors exhibiting therapeutic resistance to radiation and adjuvant chemotherapy. This review provides a comprehensive discussion of the functional involvement of caspases in apoptosis control and the current understanding of reactivating caspase-mediated apoptosis signaling towards effective therapeutic modalities in cancer treatment.

23 Review Caspase control: protagonists of cancer cell apoptosis. 2012

Fiandalo, M V / Kyprianou, N. ·Department of Molecular and Cellular Biochemistry and the Markey Cancer Center, University of Kentucky College of Medicine, Department of Urology, Lexington, KY 40536, USA. ·Exp Oncol · Pubmed #23070001.

ABSTRACT: Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

24 Review Emerging biomarkers of prostate cancer (Review). 2012

Martin, Sarah K / Vaughan, Taylor B / Atkinson, Timothy / Zhu, Haining / Kyprianou, Natasha. ·Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA. ·Oncol Rep · Pubmed #22641253.

ABSTRACT: Prostate cancer progression involves activation of signaling pathways controlling cell proliferation, apoptosis, anoikis, angiogenesis and metastasis. The current PSA-based test for the diagnosis of prostate cancer lacks sensitivity and specificity, resulting in missed diagnoses and unnecessary biopsies. Intense research efforts to identify serum and tissue biomarkers will expand the opportunities to understand the functional activation of cancer-related pathways and consequently lead to molecular therapeutic targeting towards inhibition of tumor growth. Current literature describes multiple biomarkers that indicate the properties of prostate cancer including its presence, stage, metastatic potential and prognosis. Used singly, assays detecting these biomarkers have their respective shortcomings. Several recent studies evaluating the clinical utilization of multiple markers show promising results in improving prostate cancer profiling. This review discusses the current understanding of biomarker signature cluster-based approaches for the diagnosis and therapeutic response of prostate cancer derived from panels of biomarker tests that provide a selective molecular signature characteristic of the tumor. As these signatures are robustly defined and their pathways are exhaustively dissected, prostate cancer can be more accurately diagnosed, characterized, staged and targeted with inhibitory antitumor agents. The growing promise surrounding the recent evidence in identifying and utilizing such biomarker panels, will lead to improvement in cancer prognosis and management of the therapeutic response of prostate cancer patients.

25 Review The influence of antidiabetic medications on the development and progression of prostate cancer. 2012

Hitron, Anna / Adams, Val / Talbert, Jeff / Steinke, Doug. ·Department of Pharmacy, Jewish Hospital/St. Mary's Healthcare, Louisville, KY 40202, USA. anna.hitron@jhsmh.org ·Cancer Epidemiol · Pubmed #22417708.

ABSTRACT: BACKGROUND: The development of prostate tumors has been linked to co-morbid diabetes mellitus (DM) in several studies, potentially through the stimulation of insulin-like growth factor receptor (IGFR). This study evaluates the effect of anti-diabetic medication use on the development of high grade tumors and time to tumor progression compared to non-diabetics. METHODS: This retrospective, nested case control study identified patients with prostate cancer (PCa) from the Kentucky Medicaid Database. Cases were diagnosed with PCa and DM and using at least one of the following antidiabetic medications; sulfonylureas, insulin, metformin or TZDs. Cases were further stratified on their insulin exposure resulting from therapy. Controls were those with PCa without DM or any anti-diabetic medications. RESULTS: The use of metformin or TZDs trended toward decreased odds of high-grade tumors and decreased risk of progression, while sulfonylureas and high-dose insulin tended toward an increased odds of high-grade tumors and increase the risk of progression compared to non-diabetics. CONCLUSIONS: Future studies should be conducted to further evaluate the effects of anti-diabetic medications on tumor grade and time to prostate cancer progression.

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