scholarly journals In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

2021 ◽  
Vol 7 (27) ◽  
pp. eabg2564
Author(s):  
Nathalie Bock ◽  
Thomas Kryza ◽  
Ali Shokoohmand ◽  
Joan Röhl ◽  
Akhilandeshwari Ravichandran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Adaptive Responses ◽  
Metastatic Tissue ◽  
Metastatic Lesions ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

Leveraging RB status to define therapy for castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 96-96
Author(s):  
Renee de Leeuw ◽  
Clay de Comstock ◽  
Daniela de Pollutri ◽  
Matthew Joseph Schiewer ◽  
Stephen J Ciment ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Tissue Samples ◽  
Ki67 Staining ◽  
Cell Architecture ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

96 Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.

The relationship of HIF2 and the progression of PTEN-deficient mouse prostate tumors.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 30-30
Author(s):  
W. Y. Kim ◽  
B. Zhou ◽  
G. Thomas
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Deficient Mouse ◽  
Prostate Cancer Progression ◽  
Prostate Tumors ◽  
Mesenchymal Transition

30 Background: The hypoxia-inducible factor (HIF) transcription factor has already cemented its oncogenic role in the development of renal cell carcinoma (RCC). However, its role in the tumorigenesis of other solid tumors remains unspecificed. Our studies focus on a novel link between HIF and prostate carcinogenesis. Methods: Using both in vitro cell culture studies as well as in vivo studies (orthotopic xenograft and genetically engineered mouse models) we investigate the role of HIF in prostate cancer cell proliferation, invasion, and progression. Results: Both HIF1 and HIF2 appear to be necessary for the proliferation and invasion of prostate cancer cell lines in vitro. Preliminary analysis of a PTEN deficient mouse model of prostate cancer suggests that expression of a stabilized form of HIF2 promotes the development of a larger prostate tumor burden and a more aggressive histology (high grade prostate intraepithelial neoplasia [PIN] at earlier stages). Moreover, PTEN-deficient prostate tumors producing HIF2 are more proliferative and vascular and express increased levels of genes associated with epithelial to mesenchymal transition (EMT). Conclusions: There has been much interest in the role of angiogenesis and hypoxia in prostate cancer progression. Our preliminary data suggest that HIF2 is able to promote PTEN-deficient prostate cancer progression in mice by increasing proliferation, angiogenesis, and EMT. No significant financial relationships to disclose.

Hypoxia-inducible factor 1α: A screening tool for predicting development of castrate resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15117-e15117
Author(s):  
Weranja Kalana Bodhisiri Ranasinghe ◽  
Lin Xiao ◽  
Suzana Kovac ◽  
Mike Chang ◽  
Arthur Shulkes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Screening Tool ◽  
Hypoxia Inducible Factor ◽  
Protein Translation ◽  
Lncap Cells ◽  
Free Survival ◽  
Castrate Resistant Prostate Cancer ◽  
Pc3 Cells ◽  
Castrate Resistant

e15117 Background: Currently there is no method to determine which patients starting androgen deprivation therapy (ADT) for prostate cancer (PC) will progress to castrate resistant prostate cancer (CRPC) while the reasons for early metastases and chemoresistance in CRPCs are unknown. We aimed to investigate the potential role of hypoxia inducible factor 1α (HIF1α), a key transcription factor in the cell mediated adaptive response to changes in tissue oxygenation, in predicting the development of CRPC. Methods: 100 prostate tumour samples were divided into Gleason ≤7 (38) and Gleason >7 (62) and stained for HIF1α using immunohistochemistry, blinded to the outcomes. The outcomes of CRPC, metastases and PC specific death were measured and correlated with HIF1α expression. In vitro, the effects of HIF1α on proliferation, survival and migration of PC cells were assessed by cell count and Boyden chamber assays. Results: HIF1α expression in PC was independent of Gleason grade and tumour stage. HIF1α was an independent risk factor for development of CRPC (Hazard Ratio (HR) 10.4), progression to metastases (HR 9.8) and PC specific death (HR 13.4) at median times of 23, 24 and 25 months respectively, from the start of ADT on a multivariate Cox regression analysis (all p<0.05) adjusted for Gleason score, PSA and age. CRPC free survival, metastases free survival and PC specific survival were all significantly decreased in patients with HIF1α on Kaplan Meier analyses. The presence of HIF1α was highly sensitive (all 100%) with excellent negative predictive values (all 100%) for all 3 outcomes, but had poor specificity. HIF1α over-expressing PC3 cells (CRPC) were compared with androgen sensitive LNCaP cells in vitro. PC3 cells were resistant to cytotoxic agents including H2O2 (oxidative stress) and 5-fluorouracil (chemotherapy agent) and had higher rates of migration compared to LNCaP cells. HIF1α knockdown in PC3 cells reversed these effects. Protein translation efficiency in PC3 cells was significantly higher than LNCaP cells. Conclusions: HIF1α is a good screening tool for CRPC. HIF1α expression is likely to contribute to metastases and chemoresistance of CRPCs and is likely upregulated at protein translation in PC cells.

Liquid Biopsies in Castrate-Resistant Prostate Cancer: Future Prospects in Radiation Oncology

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Carlos Galvis ◽  
María Caicedo Martinez
Keyword(s):  
Prostate Cancer ◽  
Radiation Oncology ◽  
Liquid Biopsies ◽  
Castrate Resistant Prostate Cancer ◽  
Pre Treatment ◽  
Castrate Resistant ◽  
Molecular Patterns ◽  
Available Information

The use of liquid biopsies, based on circulating tumor cells and tumoral DNA, provides information on the molecular patterns and genomics of Castrate-Resistant Prostate Cancer. There is evidence on the role of the androgen receptor variant 7 as a prognostic and as a follow-up tool, especially as a follow-up to treatment response and resistance with Enzalutamide and Abiraterone. Little is known about the genomics of Castrate Resistant Prostate Cancer and its relationship to radiation therapy’s sensibility. This is particularly relevant for patients with oligometastatic disease, who could obtain a long control of the disease with radiation. In this narrative review, we summarize the available information on liquid biopsies and Castrate Resistant Prostate Cancer. As radiation oncology evolves towards Genomically Adapted Radiation Dose, the role of liquid biopsies as a possible pre-treatment assessment is a future target. Nonetheless, models have been modeled after other malignancies. This highlights the need for further studies to assess the use of personalized medicine in these patients. Keywords: Radiotherapy; Prostate Cancer; Receptors Androgen; Liquid Biopsy; Precision Medicine;

Potential role of rituximab in metastatic castrate-resistant prostate cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 1509-1511 ◽  
Author(s):  
Poorva Bindal ◽  
Sharif AA Jalil ◽  
Lisa M Holle ◽  
Jessica M Clement
Keyword(s):  
Prostate Cancer ◽  
B Cell ◽  
Disease Progression ◽  
Androgen Deprivation ◽  
Cell Infiltration ◽  
Prostate Cells ◽  
Develop Disease Progression ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.

scholarly journals Biomarker-Based Targeting of the Androgen-Androgen Receptor Axis in Advanced Prostate Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Manish Kohli ◽  
Rui Qin ◽  
Rafael Jimenez ◽  
Scott M. Dehm
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Predictive Biomarker ◽  
Abiraterone Acetate ◽  
New Drugs ◽  
Traditional Drug ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Recent therapeutic advances for managing advanced prostate cancer include the successful targeting of the androgen-AR axis with several new drugs in castrate resistant prostate cancer including abiraterone acetate and enzalutamide (MDV3100). This translational progress from “bench to bed-side” has resulted in an enlarging repertoire of novel and traditional drug choices now available for use in advanced prostate cancer therapeutics, which has had a positive clinical impact in prolonging longevity and quality of life of advanced prostate cancer patients. In order to further the clinical utility of these drugs, development of predictive biomarkers guiding individual therapeutic choices remains an ongoing challenge. This paper will summarize the potential in developing predictive biomarkers based on the pathophysiology of the androgen-AR axis in tumor tissue from patients with advanced prostate cancer as well as inherited variation in the patient’s genome. Specific examples of rational clinical trial designs incorporating potential predictive biomarkers from these pathways will illustrate several aspects of pharmacogenetic and pharmacogenomic predictive biomarker development in advanced prostate cancer therapeutics.

scholarly journals Effect of Combination therapy of Desmopressin and Docetaxel on prostate cancer cell DU145 proliferation, migration and growth

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Azik Hoffman ◽  
Hiroshi Sasaki ◽  
Domenica Roberto ◽  
Michelle J Mayer ◽  
Laurence Klotz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wound Healing ◽  
Combination Therapy ◽  
Tumor Volume ◽  
Prostate Cancer Cell ◽  
Wound Healing Assay ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Background: This study was designed to assess the efficacy of the combination of Desmopressin and Docetaxel for prostate cancer. Desmopressin has been demonstrated to inhibit tumor progression and metastasis in in vitro and in vivo models of breast cancer. Docetaxel, an anti-mitotic chemotherapeutic agent, is widely used for the treatment of castration resistant prostate cancer. However, it is associated with adverse effects and eventual drug resistance. This is the first report on the effect of combining Desmopressin and Docetaxel in prostate cancer, both in vitro and in vivo. Methods: An established castrate resistant prostate cancer cell line DU145 was used. Cellular proliferation was determined using the MTS assay. The migratory inhibition potential of Desmopressin alone and in combination with Docetaxel was accessed using the wound healing assay. In vivo evaluation was performed on a prostate cancer xenograft model using athymic nude mouse. Treatment was administered bi- weekly and tumor volume were measured throughout the treatment period. Eventually, after a six-week treatment period, tumors were excised and measured.  Results: A combination therapy of 1 µM Desmopressin with 100nM Docetaxel resulted in dramatic inhibition of proliferation of DU145 cells 72 hours post treatment compared to either agent along (p < 0.05). Wound healing assay revealed inhibition of cellular migration as well (p<0.05). The use of a xenograft mouse model followed by treatment with 5 mg/kg Docetaxel intraperitoneally with concomitant 2 µg/ml/kg Desmopressin administered intravenously 30 minutes before administering chemotherapy and 24 hours after, resulted in a significant decrease in tumor volume (P<0.05), while not impacting body weight.Conclusions: Desmopressin significantly enhanced the anti-proliferative and inhibiting the migratory potential of Docetaxel. Combination treatment had no additional effect on mice weight or mortality. These studies could enhance the efficacy of Docetaxel- based chemotherapy treatment for castrate resistant prostate cancer.

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