scholarly journals MicroRNAs as potential therapeutics to enhance chemosensitivity in advanced prostate cancer

2018 ◽  
Author(s):  
Hui-Ming Lin ◽  
Iva Nikolic ◽  
Jessica Yang ◽  
Lesley Castillo ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Potential ◽  
Castration Resistant Prostate Cancer ◽  
Compensatory Mechanisms ◽  
Castration Resistant ◽  
Genome Wide ◽  
Taxane Resistance ◽  
A Genome ◽  
Pc3 Cells ◽  
Taxane Chemotherapy

AbstractDocetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.

scholarly journals Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
Vol 14 (10) ◽  
pp. 1020
Author(s):  
Zohaib Rana ◽  
Sarah Diermeier ◽  
Fearghal P. Walsh ◽  
Muhammad Hanif ◽  
Christian G. Hartinger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Tube Formation ◽  
In Vivo Studies ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pc3 Cells

Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models.

scholarly journals Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1285-1301
Author(s):  
Andrew J. Armstrong ◽  
Jun Luo ◽  
David M. Nanus ◽  
Paraskevi Giannakakou ◽  
Russell Z. Szmulewitz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Messenger Rna ◽  
Specific Antigen ◽  
Hormonal Treatment ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Protein Assay ◽  
Castration Resistant ◽  
Low Probability ◽  
Taxane Chemotherapy

PURPOSE Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy. PATIENTS AND METHODS PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points. RESULTS We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors. CONCLUSION Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7–positive disease still experience clinical benefits from taxane chemotherapy.

scholarly journals Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Epigenomics ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1317-1332
Author(s):  
Madonna R Peter ◽  
Misha Bilenky ◽  
Ruth Isserlin ◽  
Gary D Bader ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Cell Free Dna ◽  
Targeting Therapy ◽  
Castration Resistant ◽  
Free Dna ◽  
Aggressive Form ◽  
Genome Wide

Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Patients & methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression. Importantly, we also report that markers associated with a highly aggressive form of the disease, neuroendocrine-CRPC, were associated with a faster time to clinical progression. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

Novel monoclonal antibody therapeutics for metastatic castration resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14222-e14222
Author(s):  
Maloy Ghosh ◽  
Kavitha Iyer Rodrigues ◽  
Sunit Maity ◽  
Sanghamitra Bhattacharjee ◽  
Yogendra Manjunath ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Target Cells ◽  
Castration Resistant Prostate Cancer ◽  
Growth Reduction ◽  
Castration Resistant

e14222 Background: Therapeutic potential of innate immunity comprising Natural killer cell based targets are beginning to unravel the complexity of immune responses. NK cells recognize and induce cytotoxicity of wide range of target cells, such as, tumor cells without prior antigen sensitization. In this study, we have studied Lectin-like transcript 1 (LLT1), a member of the C-type lectin super family, is expressed on target cells and various immune cells. LLT1 isoform 1, is known to interact with CD161, a critical receptor on NK cells. CD161 is expressed on most of human NK cells, NK-T cells, γδ T cells and so on. Tumors exploit the CD161- LLT1 interaction to evade host defense mechanism (“DO NOT KILL” signal); indicating LLT1 as an attractive immunotherapeutic strategy. Methods: Prostate cancer cell lines and other tumor cell lines were used to evaluate novel anti LLT1 antibodies for therapeutic potential - IFNγ production assays and tumor cell death assays were carried out. In vivo efficacy of these antibodies were established using PC3 xenograft in humanized mouse model (HuNOG-EXL). Results: Human androgen independent prostate cancer cell line, PC3 was studied for LLT1 expression and interactions with immune cells, to understand role of LLT1 in metastatic castration resistant prostate cancer (mCRPC). Overexpression of LLT1 on tumor cells was influenced by cytokines and various TLRs. Inhibition of CD161-LLT1 interaction with novel anti LLT1 antibodies leads to IFNγ production and consequent NK cell mediated cytotoxicity – hall mark of anti-tumor responses. Disruption of LLT1 - CD161 innate immunity axis with anti LLT1 antibody releases the break on NK cell cytotoxicity and hence, established a new therapeutic option. PC3 xenograft on HuNOG mouse revealed in vivo efficacy of LLT1 antibody. Significant tumor growth reduction was observed with specific anti LLT1 antibodies alone and in combination with check point antibodies. Thus, synergistic tumor growth reduction was established by combinatorial application of anti LLT1 antibody and PD1/PDL1 axis inhibitors. Conclusions: PC3 xenograft study and other results point to therapeutic opportunities in metastatic castration resistant prostate cancer, a disease condition which needs improved patient outcomes. The ligation of CD161/LLT1 will serve as a new immuno-oncology pair regulating innate and adaptive immune responses; novel human antibodies against LLT1 described here will bring therapeutic benefit to patients in need.

scholarly journals ERG induces taxane resistance in castration-resistant prostate cancer

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Giuseppe Galletti ◽  
Alexandre Matov ◽  
Himisha Beltran ◽  
Jacqueline Fontugne ◽  
Juan Miguel Mosquera ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Taxane Resistance
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