scholarly journals Identification of tumor tissue-derived DNA methylation biomarkers for the detection and therapy response evaluation of metastatic castration resistant prostate cancer in liquid biopsies

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Thomas Dillinger ◽  
Raheleh Sheibani-Tezerji ◽  
Walter Pulverer ◽  
Ines Stelzer ◽  
Melanie R. Hassler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Tumor Tissue ◽  
Therapy Response ◽  
Response Evaluation ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Castration Resistant

Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response in castration-resistant patients.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e583-e583
Author(s):  
Camilla Thellenberg Karlsson ◽  
Lee-ann Tjon-Kon-Fat ◽  
Marie Lundholm ◽  
Mona Schröder ◽  
Thomas Wurdinger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Best Practice ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Therapy Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Biomarker Analysis

e583 Background: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance. Methods: The isolated platelet population of blood samples and QRT-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis directed therapies. The association between biomarker status in platelets (positive vs. negative) and therapy response, progression-free survival (PFS) and overall survival (OS) was examined. Results: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-3 ( KLK3), androgen receptor splice-variant 7 (ARV7), folate hydrolase 1 (FOLH1), and neuropeptide-Y ( NPY) were present within the platelet fraction. Analyzing biomarkers in the chemotherapy group did not add information about PFS, but FOLH1 was associated with short OS (p = 0.00015). In the abiraterone treated cohort, detectable FOLH1 (p = 0.009), KLK3 (p = 0.018), and NPY (p = 0.028) were all associated with short PFS. Patients with biomarker-negative platelets had the best outcome, while FOLH1 and NPY provided independent predictive information regarding PFS and KLK3 (p = 0.001) and FOLH1 (p = 0.002) were associated with short OS. Conclusions: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with high accuracy. Platelet-based analysis of FOLH1, NPY, and KLK3 may be used for treatment stratification of patients scheduled for treatment with abiraterone.

scholarly journals Prediction of response and survival after standardized treatment with 7400 MBq 177Lu-PSMA-617 every 4 weeks in patients with metastatic castration-resistant prostate cancer

2020 ◽  
Author(s):  
Sazan Rasul ◽  
Markus Hartenbach ◽  
Tim Wollenweber ◽  
Elisabeth Kretschmer-Chott ◽  
Bernhard Grubmüller ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Median Survival ◽  
Therapy Response ◽  
Binary Logistic Regression ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Regimens ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Standardized Treatment

Abstract Background and aims [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks. Patients and methods Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0–4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS). Results Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09–2.09) with an AUC of 0.68 (95% CI: 0.54–0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09–2.09 and 0.43–1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT. Conclusion Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.

scholarly journals Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma

BMJ Open ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. e039639
Author(s):  
Jonas S Heitmann ◽  
Juliane S Walz ◽  
Martin Pflügler ◽  
Joseph Kauer ◽  
Richard F Schlenk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Time Course ◽  
Tumour Response ◽  
Maximum Tolerated Dose ◽  
University Hospital ◽  
Inpatient Setting ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Multicentre Phase ◽  
Castration Resistant

IntroductionProstate cancer is the second most common cancer in men worldwide. When the disease becomes resistant to androgen-deprivation therapy, treatment options are sparse. To address the high medical need in castration-resistant prostate cancer (CRPC), we generated a novel PSMAxCD3 bispecific antibody termed CC-1. CC-1 binds to prostate-specific membrane antigen that is expressed on prostate cancer cells and tumour vessels, thereby allowing a dual anticancer effect.Methods and analysisThis first in human clinical study is a prospective and multicentre trial which enrols patients with metastatic CRPC after failure of established third-line therapy. CC-1 is applied after prophylactic interleukin-6 receptor blockade with tocilizumab (once 8 mg/kg body weight). Each patient receives at least one cycle of CC-1 over a time course of 7 days in an inpatient setting. If clinical benefit is observed, up to five additional cycles of CC-1 can be applied. The study is divided in two parts: (1) a dose escalation phase with intraindividual dose increase from 28 µg to the target dose of 1156 µg based on a modified fast titration design by Simon et al to determine safety, tolerability and the maximum tolerated dose (MTD) as primary endpoints and (2) a dose expansion phase with additional 14 patients on the MTD level of part (1) to identify first signs of efficacy. Secondary endpoints compromise overall safety, tumour response, survival and a translational research programme with, among others, the analysis of CC-1 half-life, the induced immune response, as well as the molecular profiling in liquid biopsies.Ethics and disseminationThe PSMAxCD3 study was approved by the Ethics Committee of The University Hospital Tübingen (100/2019AMG1) and the Paul-Ehrlich-Institut (3684/02). Clinical trial results will be published in peer-reviewed journals.Trial registration numbersClinicalTrials.gov Registry (NCT04104607) and ClinicalTrials.eu Registry (EudraCT2019-000238-20).

Combinatorial expression of androgen receptor splice variants: No predictive value in castration-resistant prostate cancer patients treated with enzalutamide (enza) or abiraterone (abi).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17547-e17547
Author(s):  
Katrin Schlack ◽  
Konstantin Seitzer ◽  
Martin Boegemann ◽  
Laura-Maria Krabbe ◽  
Andres Jan Schrader ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variant ◽  
Predictive Power ◽  
Splice Variants ◽  
Statistical Significance ◽  
Therapy Response ◽  
Hormonal Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

e17547 Background: Playing an important role in prostate cancer, androgen receptor (AR) signaling is a common therapeutic target. Novel hormonal treatment (NHT) using enza or abi prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, biomarkers predicting therapy response are limited. AR-V7, as the most abundant AR splice variant, has gained clinical interest. Nonetheless, current discussions on its predictive power are diverse. Given that AR-V7 as a sole biomarker is not efficient in predicting response to NHT, we aimed to increase the predictive potential by analysis of combinatorial AR splice variant (AR-V) expression in mCRPC patients undergoing NHT. Methods: We prospectively enrolled 60 patients who started on either abi or enza. Presence of circulating tumor cells (CTC) as well as expression of AR-V3, -7 and -9 were assessed. Outcomes in CTC-, CTC+/AR-V- and CTC+/AR-V+ patients were analyzed considering PSA reduction, PSA-PFS, PFS and OS. Results: PSA reduction of 50% was predominantly found in CTC- patients (78.5%) compared to CTC+/AR-V- (55.5%) and CTC+/AR-V+ (39.3%) without statistical significance (P = 0.059). When taking co-expression of two or more AR-V into account there was no difference in PSA response either (one AR-V 42.9%, two AR-V 33.3%, three AR-V 41.6%, P = 0.154). Median PSA-PFS was 17 months (95%CI 15.7 – 18.3), 13 months (95%CI 6.8 – 19.2) and 5 months (95%CI 3.6 – 6.4) for CTC- pts, CTC+/AR-V- pts and CTC+/AR-V+ pts, respectively (P = 0.005). However, comparing CTC- and CTC+ pts, differences become even more apparent (P = 0.004), CTC+/AR-V- and AR-V+ pts showed less statistically significant differences (P = 0.029). Median PFS and OS were not reached for CTC- pts. PFS was 10 months (95%CI 6.2 – 13.8) for CTC+/AR-V- pts and 9 months (95%CI 1.1 – 16.9) for CTC+/AR-V+ pts (P = 0.004, only CTC- vs. CTC+ P = 0.002). OS was 28 months (95%CI 16.8 – 39.2) for CTC+/AR-V- pts and 15 months (95%CI 7.9 – 22.1) for CTC+/AR-V+ pts (P = 0.014, only CTC- vs. CTC+ P = 0.006). Regarding PFS and OS, there was no difference comparing only CTC+/AR-V- and AR-V+ pts (P = 0.356 and P = 0.244). Conclusions: AR splice variants have prognostic power in stratifying mCRPC patients suffering from a more advanced stage of disease. Nonetheless, our study clearly demonstrates the lack of predictive power of AR splice variants for response to NHT. Additionally, we prove the importance of CTC analysis rather than AR-V expression being more valuable in mCRPC.

Ultrasound-Induced Microbubble Cavitation Combined with miR-34a-Loaded Nanoparticles for the Treatment of Castration-Resistant Prostate Cancer

2021 ◽  
Vol 17 (1) ◽  
pp. 78-89
Author(s):  
Ziqi Wang ◽  
Chuanrong Chen ◽  
Yuchen Tao ◽  
Penglin Zou ◽  
Feng Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Side Effects ◽  
Tumor Tissue ◽  
Cell Membrane Permeability ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
First Line ◽  
Chemotherapy Drugs ◽  
Castration Resistant ◽  
Methoxy Polyethylene Glycol

Currently chemotherapy drugs are usually used as first-line treatments for castration-resistant prostate cancer (CRPC), but they are ineffective and accompanied by serious side effects. MicroRNA-34a (miR-34a) simultaneously targets multiple genes related to the cell apoptosis in CRPC cells without obvious side effects. It has shown great potential in the treatment of CRPC. Previous studies focused on miR-34a increasing the sensitivity of chemotherapy drugs to chemoresistant prostate cancer cells. There are few researches on miR-34a alone in the treatment of CRPC. But the macromolecular miR-34a is difficult to enter the cell and is easily degraded by nuclease. Therefore, we constructed methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) nanoparticles to encapsulate miR-34a (miR-34a/NP). The results showed that miR-34a/NP protects miR-34a from degradation by nucleases and can be phagocytized by PC-3 CRPC cells. Ultrasound induces microbubble cavitation (UIMC) improves cell membrane permeability and capillary gaps, and further promotes miR-34a/NP to enter cells PC-3 and prostate cancer xenografts. The miR-34a/NP that enters the cell and tumor tissue releases miR-34a, which suppressed CRPC cells PC-3 proliferation, promoted its apoptosis, and inhibited the growth of CRPC xenografts. Our research verified that miR-34a/NP, especially combined with UIMC, has a significant anti-tumor effect on CRPC.

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