scholarly journals Targeting RET Kinase in Neuroendocrine Prostate Cancer

2019 ◽  
Author(s):  
Halena VanDeusen ◽  
Johnny R. Ramroop ◽  
Katherine L. Morel ◽  
Anjali V Sheahan ◽  
Zoi Sychev ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Treatment Options ◽  
Kinase Signaling ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Novel Approach ◽  
Neuroendocrine Prostate Cancer ◽  
Aggressive Variant

AbstractIncreased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression and may be a novel treatment option.Statement of SignificanceThere are limited treatment options for patients with metastatic aggressive variant prostate cancer and none are curative. Here we identified aberrantly activated RET kinase signaling in multiple models of NEPC. Inhibiting RET restricted tumor growth, providing a novel approach for treating NEPC.

scholarly journals Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhoulei Li ◽  
Peng He ◽  
Yali Long ◽  
Gang Yuan ◽  
Wanqing Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin C ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Combined Treatment ◽  
Drug Repurposing ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
18F Fdg

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

scholarly journals Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Divya Bhagirath ◽  
Michael Liston ◽  
Theresa Akoto ◽  
Byron Lui ◽  
Barbara A. Bensing ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Neuroendocrine Differentiation ◽  
Extracellular Vesicle ◽  
Machine Learning Algorithms ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Non Invasive ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

scholarly journals Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

2020 ◽  
Vol 148 (2) ◽  
pp. 385-395
Author(s):  
Peter H. J. Slootbeek ◽  
Marleen L. Duizer ◽  
Maarten J. Doelen ◽  
Iris S. H. Kloots ◽  
Malou C. P. Kuppen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Repair ◽  
Aggressive Variant

Treatment Given Near the End of Life in Castration-Resistant Prostate Cancer

2012 ◽  
Vol 29 (7) ◽  
pp. 536-540 ◽  
Author(s):  
Hanna A. Zaghloul ◽  
Jose R. Murillo
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
End Of Life ◽  
Treatment Options ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Related Quality ◽  
Impact On Survival ◽  
New Treatments

Chemotherapy treatment options are limited for patients with castration-resistant prostate cancer (CRPC). The purpose of this study is to report treatment use and adverse effects (AEs) within the last three months of life in patients with CRPC. Of the 88 patients identified, 32% received treatment within 3 months of death, and documented AEs occurred in 25% of patients. Of those, neutropenia (18.3%), nausea/vomiting (18.3%), and febrile neutropenia (13.6%) were the most frequent. Results of this study show high treatment utility towards the end-of-life in patients with CRPC, with one fourth of patients experiencing AEs. Attention to health-related quality of life becomes increasingly important as new treatments appear to have small impact on survival, and AEs of those treatments may significantly impact patient quality of life.

scholarly journals Clinicopathologic Diagnostic Approach to Aggressive Variant Prostate Cancer

2019 ◽  
Vol 144 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Varsha Manucha ◽  
John Henegan
Keyword(s):  
Prostate Cancer ◽  
English Language ◽  
Treatment Strategies ◽  
Castration Resistant Prostate Cancer ◽  
Ongoing Research ◽  
Castration Resistant ◽  
Current Review ◽  
Pathologic Features ◽  
Neuroendocrine Carcinomas ◽  
Aggressive Variant

Context.— Aggressive variant prostate cancer (AVPCa) develops in a subset of patients with metastatic castration-resistant prostate cancer. The clinical and histologic overlap of AVPCa with other neuroendocrine carcinomas of the prostate has resulted in a lack of consensus on its terminology and treatment. Objective.— To review AVPCa to familiarize pathologists with this entity so they can actively participate in the detection, ongoing research, and evolving management of AVPCa. Data Sources.— The English language literature was reviewed. Conclusions.— The current review summarizes the pathologic features of AVPCa, describes how it has been defined clinically, and discusses how biomarkers may inform treatment strategies in the future.

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