scholarly journals Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

2021 ◽  
Author(s):  
Aerken Maolake ◽  
Renyuan Zhang ◽  
Kai Sha ◽  
Shalini Singh ◽  
Chunliu Pan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Human Prostate ◽  
Murine Models ◽  
Castration Resistant Prostate Cancer ◽  
High Frequency Ultrasound ◽  
Over Expression ◽  
Castration Resistant ◽  
Glucocorticoid Signaling ◽  
Prostate Cancer Therapy ◽  
Prostate Cancers

Androgen deprivation therapy (ADT) is the mainstay therapy for recurrent and advanced prostate cancer. While human prostate cancers initially regress following ADT, many tumors fail this therapy and recur. To understand the response of prostate cancers to ADT, we have employed high frequency ultrasound imaging to track the kinetics of tumor volume in murine models of prostate cancer. Previously, we showed that normal (non-tumor) prostate regression begins within two days of castration. Following castration, murine prostate cancers also regress but only after a delay of 3-14 days, dependent on initial tumor size. Delayed regression is observed in two distinct mouse models (MYC over-expression, PTEN-deficient) implying that the genetic lesion which initiates carcinogenesis does not play a role. Intra-tumoral androgen levels are undetectable 16 hours post-castration, arguing that residual androgen signaling is not the cause of delayed regression. Castration induces tumor cell proliferation during this period. There is an increase in the active glucocorticoids, as well as glucocorticoid receptor (GR) mRNA and protein and a set of GR-regulated genes. A selective GR inhibitor eliminates the delayed regression phenotype in both models. Thus, GR signaling is activated following castration and transiently enhances tumor proliferation. This response to ADT resembles the GR-dependent mechanism of escape for prostate cancers that are resistant to anti-androgen therapies and may provide mechanistic insight into the development of castration resistant prostate cancer. If ADT-induced GR signaling is similar in human prostate cancers, simultaneous blockade of GR and androgen receptor signaling could improve prostate cancer therapy.

Novel biomarker of specific castration-resistant prostate cancer (CRPC) by exploring the proteome analysis.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 247-247 ◽  
Author(s):  
Hiroji Uemura ◽  
Noriaki Arakawa ◽  
Yusuke Itoh ◽  
Takashi Kawahara ◽  
Yasuhide Miyoshi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Proteome Analysis ◽  
Human Prostate ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Prostate Hyperplasia ◽  
Castration Resistant ◽  
Significant Difference ◽  
Prostate Cancers

247 Background: It is well known that prostate specific antigen (PSA) level has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for the development of castration resistant prostate cancer (CRPC). The aim of this study is to explore novel biomarkers to predict the development of CRPC by using proteomics from secreted proteins from human prostate cancer cells. Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDDP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDDP, was significantly higher in CRPC than those in BPH and untreated PCa (P < 0.01). ROC analysis also showed that the AUC of GDDP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDDP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDDP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDDP-1 may be a novel biomarker for CRPC. Conclusions: GDDP-1 shows potential as a novel biomarker for CRPC.

Sex Hormones and Prostate Cancer

2020 ◽  
Vol 71 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Richard J. Auchus ◽  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Current Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
History Of ◽  
Prostate Cancer Research ◽  
Prostate Cancers ◽  
Androgen Independent ◽  
Transition Studies

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 17-17
Author(s):  
Z. Liao ◽  
L. Gu ◽  
F. Shen ◽  
A. Dagvadorj ◽  
S. Gupta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Human Prostate ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Molecule Inhibitor ◽  
Prostate Cancers

17 Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer. Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay. Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures. Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration. No significant financial relationships to disclose.

scholarly journals Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response

2020 ◽  
Author(s):  
Matthew J Mosquera ◽  
Rohan Bareja ◽  
Jacob M Bernheim ◽  
Muhammad Asad ◽  
Cynthia Cheung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inflammatory Cells ◽  
Cellular Reprogramming ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Prostate Cells ◽  
Synthetic Hydrogel ◽  
Neuroendocrine Prostate Cancer ◽  
Prostate Cancers ◽  
Novel Target

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

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