scholarly journals HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

2022 ◽  
Author(s):  
Bernhard Biersack ◽  
Bianca Nitzsche ◽  
Michael Höpfner
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Anticancer Drugs ◽  
Synergistic Effects ◽  
Hdac Inhibitors ◽  
Resistance Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Combination Treatments ◽  
Castration Resistant ◽  
The One

Epigenetic mechanisms play an important role in the development and persistence of cancer, and histone deacetylase (HDAC) inhibitors are promising anticancer drugs targeting epigenetic modes. Efficient anticancer drugs for the treatment of castration-resistant prostate cancer (CRPC) are sought, and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand. Hence, ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance. In this work, HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.

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.

Salvage chemotherapy with cisplatin, ifosfamide, and paclitaxel in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 123-123
Author(s):  
Gunhild Von Amsberg ◽  
Mirjam Zilles ◽  
Philipp Gild ◽  
Winfried Alsdorf ◽  
Lukas Boeckelmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Synergistic Effects ◽  
Antagonistic Effect ◽  
University Hospital ◽  
Additive Effects ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Platinum Based Chemotherapy ◽  
Wide Range

123 Background: Recent developments in the treatment of metastatic castration resistant prostate cancer (mCRPC) lead to a revival of platinum-based chemotherapy demonstrating increased activity in patients with aggressive variants of disease. Here, we report on the results of a combinational salvage therapy with cisplatin, ifosfamide and paclitaxel (TIP) in mCRPC. Methods: We retrospectively analyzed patients with mCRPC treated with TIP at the University Hospital Hamburg-Eppendorf between November 2013 and September 2020. Accompanying in vitro analyses were performed using human prostate carcinoma cell lines harboring different levels of drug resistance including the docetaxel-resistant sublines PC3-DR and DU45-DR. Results: In total, 17 mCRPC patients treated with TIP were eligible for efficacy analyses with a median age of 65 yrs. At baseline, liver metastases were present in 88%, metastases of other visceral sides (lung, adrenal gland, brain) in 47% and bone metastases in 76% of the patients. Median hemoglobin was 9.8mg/dl, LDH 903 U/l and AP 205 U/l. Median PSA value was 77 ng/ml covering a wide range including three patients with a PSA-value below 1ng/ml. NSE was evaluated in 83% of the patients (median 38,5 U/l). Patients were extensively pretreated with a median of three treatment lines before TIP (100% docetaxel, 82% abirateron and/or enzalutamide, 47% cabazitaxel, 41% others). A median of 3,5 cycles of TIP were applied with 29% of the patients receiving the maximum of 6 cycles. Four patients discontinued treatment due to side effects (PNP, infection, ifosfamide induced psychosis). At interim analyses, 59 % of the patients showed a radiological response or stable disease with only one patient progressing till the end of treatment. Median PFS was 2.5 months, median OS 6 months. A decrease of PSA > 30% and LDH > 50% was observed in 41% and 35% of the patients, respectively. In vitro experiments revealed additive effects of TIP in 22Rv1, LNCaP and DU45 cells and synergistic effects in neuroendocrine LASCPC-01 cells. In PC3 cells, TIP induced antagonistic effects at lower doses, whereas dose-independent additive effects were observed in docetaxel-resistant PC3-DR. Surprisingly, preliminary data of combined therapies with different drug pairs suggest an antagonistic effect of paclitaxel in the combination with both, cisplatin and ifosfamide. Conclusions: Combinational therapy with cisplatin, ifosfamide and paclitaxel showed promising activity in some patients with aggressive mCRPC. Preclinical data suggest that the drug combination of cisplatin and ifosfamide rule the efficacy of TIP in mCRPC.

Activity of gemcitabine-oxalipaltin (GemOx) plus prednisolone in patients with castration-resistant prostate cancer (CRPC) for whom docetaxel-based chemotherapy failed.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 108-108
Author(s):  
Jae-Lyun Lee ◽  
Yesul Kim ◽  
Jin-Hee Ahn ◽  
MeeKyung Choi ◽  
Seung-Woo Hong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Drug Effects ◽  
Fixed Dose ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Psa Progression ◽  
Grade 3

108 Background: We assessed the cytotoxic effects of the gemcitabine in combination with oxaliplatin (GemOx) in prostate cancer cell lines and evaluated the efficacy and safety of GemOx in patients with metastatic castration-resistant prostate cancer (CRPC) who failed docetaxel based chemotherapy. Methods: Gemcitabine and oxaliplatin were preclinically tested for their cytotoxic activity in LNCaP, PC3 and DU145 cell lines. The combined drug effects were evaluated using the Chou and Taladay analysis. Clinically, patients with CRPC who failed prior docetaxel chemotherapy were treated with gemcitabine 1,000 mg/m2 at fixed-dose rate (10 mg/m2/min) and oxaliplatin 100 mg/m2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. Unless disease progression or intolerability develops, treatment could be continued until 12 cycles. Primary endpoint was PSA response rate (PCWG 1.0 criteria). Results: The IC50of gemcitabine and oxaliplatin were, respectively, 1.25 μM and 0.69 μM for LNCaP cells; 50.00+ μM and 12.81 μM for PC3 cells; and 11.23 μM and 11.04 μM for DU145 cells. The GemOx combination displayed synergistic effects in all 3 cell lines. In phase II study, 31 patients were accrued. At the time of this analysis 7 patients were still continuing treatment. The median age was 67 years (range 57 ~ 81) and the median dose of docetaxel exposure was 525 mg/m2. A total of 231 cycles administered with a median of 9 cycles per patient. PSA responses were observed in 52% (95% CI, 34~69) and partial responses were observed in 7 of 10 patients with measurable disease. Out of 23 patients, 10 patients achieved pain response (44%). With a median FU duration of 8.0 months, the median time to PSA progression was 6.4 months (95% CI, 3.5~9.2). Peripheral neuropathy developed in 78% of patients but remained of grade 1 ~2 intensities. Frequently observed grade 3 or 4 toxicities were neutropenia (10%), thrombocytopenia (10%), anemia (3%), and diarrhea (3%). Conclusions: GemOx is active and well tolerated in patients with CPRC after docetaxel failure and deserves further investigation in this setting (NCT 01487720). Clinical trial information: NCT01487720.

A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Pai-Chi Teng ◽  
Yu Jen Jan ◽  
Junhee Yoon ◽  
Pin-Jung Chen ◽  
Jie-Fu Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Circulating Tumor Cell ◽  
Z Score ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.

Optic atrophy after cabazitaxel treatment in a patient with castration-resistant prostate cancer: a case report

2018 ◽  
Vol 64 (2) ◽  
pp. 71-73 ◽  
Author(s):  
Sevda Diker ◽  
Ömer Diker
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Case Report ◽  
Adverse Effects ◽  
Optic Neuropathy ◽  
Optic Atrophy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Cancer ◽  
New Generation

Taxanes are a group of cytotoxic anti-cancer agents used in the treatment of solid tumours. The neurotoxic adverse effects of docetaxel and paclitaxel, including optic neuropathy, are well known. Cabazitaxel is a new generation taxane showing lesser drug resistance when compared with previous ones. Optic atrophy due to the use of cabazitaxel has not been previously reported. Herein, we report a patient with prostate cancer who developed optic atrophy after cabazitaxel treatment.

scholarly journals Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer

2017 ◽  
pp. 1-11 ◽  
Author(s):  
G. Celine Han ◽  
Justin Hwang ◽  
Stephanie A.M. Wankowicz ◽  
Zhenwei Zhang ◽  
David Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Deprivation Therapy ◽  
Second Generation ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Line Of Therapy

Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A ( CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade—palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

scholarly journals A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2247
Author(s):  
Lilli Hofmann ◽  
Katja Sallinger ◽  
Christoph Haudum ◽  
Maria Smolle ◽  
Ellen Heitzer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Liquid Biopsy ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Related Information ◽  
Castration Resistant ◽  
Signaling Inhibitors

Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.

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