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.

Expression pattern of androgen receptors, AR-V7 and AR-567es, in circulating tumor cells and paired plasma-derived extracellular vesicles in metastatic castration resistant prostate cancer

The Analyst ◽  
2019 ◽  
Vol 144 (22) ◽  
pp. 6671-6680 ◽  
Author(s):  
Areti Strati ◽  
Martha Zavridou ◽  
Evangelos Bournakis ◽  
Sophia Mastoraki ◽  
Evi Lianidou
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Androgen Receptors ◽  
Acquired Resistance ◽  
Predictive Biomarker ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Inhibitors ◽  
Androgen Receptor Splice Variant

Androgen-receptor splice variant 7 (AR-V7) is a highly promising liquid biopsy predictive biomarker showing primary or acquired resistance to novel androgen receptor signaling inhibitors in metastatic castration resistant prostate cancer (mCRPC).

scholarly journals Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 860 ◽  
Author(s):  
Jacob J. Adashek ◽  
Rohit K. Jain ◽  
Jingsong Zhang
Keyword(s):  
Prostate Cancer ◽  
Unmet Need ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Signaling Inhibitors

The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.

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).

Degradation of Androgen Receptor through Small Molecules for Prostate Cancer

2018 ◽  
Vol 18 (7) ◽  
pp. 652-667 ◽  
Author(s):  
Raoling Ge ◽  
Xi Xu ◽  
Pengfei Xu ◽  
Lei Li ◽  
Zhiyu Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Small Molecules ◽  
Androgen Deprivation Therapy ◽  
Resistance Mechanism ◽  
Androgen Deprivation ◽  
High Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Androgen Receptor Antagonists

Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer.

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