scholarly journals Novel Therapeutic Approaches to Overcome Acquired Resistance to Enzalutamide in Patients with Advanced Prostate Cancer

10.33540/325 ◽  
2020 ◽  
Author(s):  
◽  
Keith Thomas Schmidt Schmidt
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Therapeutic Approaches ◽  
Novel Therapeutic

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 25-25
Author(s):  
Hanna Tukachinsky ◽  
Russell Madison ◽  
Jon Chung ◽  
Lucas Dennis ◽  
Bernard Fendler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
High Level ◽  
Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

scholarly journals Molecular Mechanisms Related to Hormone Inhibition Resistance in Prostate Cancer

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 43 ◽  
Author(s):  
Veronica Mollica ◽  
Vincenzo Di Nunno ◽  
Alessia Cimadamore ◽  
Antonio Lopez-Beltran ◽  
Liang Cheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Molecular Mechanisms ◽  
High Sensitivity ◽  
New Drugs ◽  
Prostate Cancer Cells ◽  
Therapeutic Approaches ◽  
Hormone Production ◽  
Development Of Resistance ◽  
History Of

Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or binding to nuclear receptor have been evaluated and adopted in clinical practice. However, despite several hormonal treatments being available nowadays for the management of advanced or metastatic prostate cancer, the natural history of the disease leads inexorably to the development of resistance to hormone inhibition. Findings regarding the mechanisms that drive this process are of particular and increasing interest as these are potentially related to the identification of new targetable pathways and to the development of new drugs able to improve our patients’ clinical outcomes.

scholarly journals Novel therapeutic approaches for the treatment of castration-resistant prostate cancer

2013 ◽  
Vol 138 ◽  
pp. 248-256 ◽  
Author(s):  
Isabel Heidegger ◽  
Petra Massoner ◽  
Iris E. Eder ◽  
Andreas Pircher ◽  
Renate Pichler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Therapeutic Approaches ◽  
Castration Resistant ◽  
Novel Therapeutic

Clinical Trial Update and Novel Therapeutic Approaches for Metastatic Prostate Cancer

2011 ◽  
Vol 18 (29) ◽  
pp. 4440-4453 ◽  
Author(s):  
R. Larsson ◽  
N. P. Mongan ◽  
M. Johansson ◽  
L. Shcherbina ◽  
P.-A. Abrahamsson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Metastatic Prostate Cancer ◽  
Therapeutic Approaches ◽  
Novel Therapeutic

scholarly journals AR mRNA stability is increased with AR-antagonist resistance via 3′UTR variants

2020 ◽  
Vol 9 (1) ◽  
pp. 9-19 ◽  
Author(s):  
D A Dart ◽  
K Ashelford ◽  
W G Jiang
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Mrna Stability ◽  
Advanced Prostate Cancer ◽  
Actinomycin D ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Rna Seq ◽  
Serum Samples ◽  
Mrna Variant

Advanced prostate cancer is often treated with AR antagonists which target the androgen receptor (AR) on which the growth of the tumour depends. Prostate cancer often develops AR-antagonist resistance via a plethora of mechanisms, many of which are as yet unknown, but it is thought that AR upregulation or AR ligand-binding site mutations, may be responsible. Here we describe the production of cell lines based on LNCaP and VCaP, with acquired resistance to the clinically relevant AR antagonists, bicalutamide and enzalutamide. In these resistant cells, we observed, via RNA-seq, that new variants in the 3′UTR of the AR mRNA were detectable and that the levels were increased both with AR-antagonist treatment and with hormonal starvation. Around 20% of AR transcripts showed a 3 kb deletion within the 6.7 kb 3′UTR sequence. Actinomycin D and luciferase fusion studies indicated that this shorter mRNA variant was inherently more stable in anti-androgen-resistant cell lines. Of additional interest was that the AR UTR variant could be detected in the sera of prostate cancer patients in a cohort of serum samples collected from patients of Gleason grades 6–10, with an increasing level correlated to increasing grade. We hypothesise that the shorter AR UTR variant is a survival adaptation to low hormone levels and/or AR-antagonist treatment in these cells, where a more stable mRNA may allow higher levels of AR expression under these conditions.

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