Discovering Therapeutic Protein Targets for Bladder Cancer Using Proteomic Data Analysis

2020 ◽  
Vol 13 (2) ◽  
pp. 150-172 ◽  
Author(s):  
Samira Bahrami ◽  
Bahram Kazemi ◽  
Hakimeh Zali ◽  
Peter C. Black ◽  
Abbas Basiri ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Gene Ontology ◽  
Monoclonal Antibodies ◽  
Membrane Proteins ◽  
Growth Factor Receptor ◽  
Subcellular Location ◽  
Cancer Tissue ◽  
Heat Shock Protein 60 ◽  
Absolute Quantitation ◽  
Muscle Invasive

Background: Bladder cancer accounts for almost 54% of urinary system cancer and is the second most frequent cause of death in genitourinary malignancies after prostate cancer. About 70% of bladder tumors are non-muscle-invasive, and the rest are muscle-invasive. Recurrence of the tumor is the common feature of bladder cancer. Chemotherapy is a conventional treatment for MIBC, but it cannot improve the survival rate of these patients sufficiently. Therefore, researchers must develop new therapies. Antibody-based therapy is one of the most important strategies for the treatment of solid tumors. Selecting a suitable target is the most critical step for this strategy. Objective: The aim of this study is to detect therapeutic cell surface antigen targets in bladder cancer using data obtained by proteomic studies. Methods: Isobaric tag for relative and absolute quantitation (iTRAQ) analysis had identified 131 overexpressed proteins in baldder cancer tissue and reverse-phase proteomic array (RPPA) analysis had been done for 343 tumor tissues and 208 antibodies. All identified proteins from two studies (131+208 proteins) were collected and duplicates were removed (331 unique proteins). Gene ontology study was performed using gene ontology (GO) and protein analysis through evolutionary relationships (PANTHER) databases. The Human Protein Atlas database was used to search the protein class and subcellular location of membrane proteins obtained from the PANTHER analysis. Results: Membrane proteins that could be suitable therapeutic targets for bladder cancer were selected. These included: Epidermal growth factor receptor (EGFR), Her2, Kinase insert domain receptor (KDR), Heat shock protein 60 (HSP60), HSP90, Transferrin receptor (TFRC), Activin A Receptor Like Type 1 (ACVRL1), and cadherin 2 (CDH2). Monoclonal antibodies against these proteins or their inhibitors were used for the treatment of different cancers in preclinical and clinical trials. Conclusion: These monoclonal antibodies and inhibitor molecules and also their combination can be used for the treatment of bladder cancer.

scholarly journals Research on new drugs in the therapy of bladder cancer (BC)

2018 ◽  
Vol 72 ◽  
pp. 442-448 ◽  
Author(s):  
Karolina Jurkowska ◽  
Anna Długosz
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
New Drugs ◽  
Muscle Invasive Bladder Cancer ◽  
Epidermal Growth ◽  
Muscle Invasive

New, more effective and safer therapies in bladder cancer are being developed. Most attention is focused on monoclonal antibody therapies, targeted therapies and immunotherapy. Numerous pre-clinical and clinical studies on the use of the new drugs in bladder cancer are currently in progress. The great hope is associated with monoclonal antibodies, which are immune checkpoint inhibitors. Last year, two drugs from this group (Atezolizumab and Nivolumab) have been approved by Food and Drug Administration (FDA) for the treatment of muscle invasive bladder cancer (MIBC). Other monoclonal antibodies in this group such as Pembrolizumab are also in clinical trials. Much attention is also focused on targeted therapies. Inhibitors of: VEGF (vascular endothelial growth factor), EGFR (epidermal growth factor receptor), HER-2 (human epidermal growth factor receptor 2) and mTOR kinase are examined in bladder cancer. These drugs are often studied as a combination therapy with chemioterapeutic agents. Alternatives for BCG (Bacillus Calmette-Guérin) therapy in non muscle invasive bladder cancer (NMIBC) are also being developed. Research on the use of new vaccines and other immunotherapies (e.g. IL-12 therapy) are underway. The aim of this paper is to present the direction of current trends in bladder cancer treatment and what changes in therapy we can expect in the future. The drugs in clinical trials and those already registered in other countries have been reviewed. The latest drug-based therapeutic solutions have been described, which can replace traditional chemotherapy in the future.

Development of a novel immunotherapy for muscle invasive bladder cancer (MIBC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 402-402
Author(s):  
Irina Y. Tcherepanova ◽  
Bradley C. Leibovich ◽  
Jacoba Slagter-Jager ◽  
Patrick Dillon ◽  
Shawn Michael Leland ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Rna Extraction ◽  
Rna Degradation ◽  
Invasive Bladder Cancer ◽  
Cancer Tissue ◽  
Autologous Tumor ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Tissue ◽  
Bladder Cancer Tissue ◽  
Muscle Invasive

402 Background: AGS-003 is an autologous tumor RNA-loaded dendritic cell-based immunotherapy being tested in advanced renal cell carcinoma (RCC) patients. The immunologic specificity for the patient’s own tumor is achieved using amplified tumor RNA electroporated into monocyte derived dendritic cells. To produce AGS-003 for RCC patients the RNA is amplified from a 100 mg primary tumor sample obtained via nephrectomy. In this non treatment study we evaluated the feasibility of RNA amplification from MIBC tissue acquired by transurethral resection of bladder tumor (TURBT). Methods: MIBC tissue was obtained via TURBT. Following draining of the irrigant used during the TURBT procedure, tissue was placed into an RNA preservative solution to prevent RNA degradation until processing. Methods developed for the amplification of RCC tumor RNA and RNA quality testing were applied to the RNA extracted from the MIBC specimens. Results: This work demonstrated that the methods developed for the amplification and testing of RNA from RCC can be successfully employed for the amplification of RNA from MIBC specimens collected by TURBT. Results demonstrated that the total RNA yields obtained from bladder tissue exceed that of similar masses of primary RCC tumors. This finding enabled the reduction in the amount of starting material from 100 mg to 50 mg of bladder tissue. The amount of amplified RNA produced from the lower bladder cancer masses were sufficient to support the production of immunotherapy at full scale (17 doses average). Conclusions: These data demonstrate the feasibility of RNA extraction and amplification from muscle invasive bladder cancer tissue and supports our planned phase II clinical study. [Table: see text]

MYC gene copy number (GCN) and sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21018-e21018
Author(s):  
Armida D'Incecco ◽  
Lorenza Landi ◽  
George Fountzilas ◽  
Konstantine T. Kalogeras ◽  
Ravit Geva ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Rare Event ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Gene Copy ◽  
Cancer Tissue ◽  
Tissue Samples ◽  
Myc Gene

e21018 Background: Monoclonal antibodies against Epidermal Growth Factor Receptor (EGFR) demonstrated efficacy in mCRC patients without mutations in the KRAS gene. Previous data in breast and lung cancer suggested that MYC GCN affects sensitivity to anti-EGFR agents. Methods: This retrospective study was conducted in a cohort of 303 mCRC patients treated with cetuximab/panitumumab, either alone (N=24) or in combination with chemotherapy (N=279). MYC GCN was assessed by fluorescence in situ hybridization (FISH) in primary colorectal cancer tissue samples. Results: In the study population response rate (RR) was 28%, median progression-free survival (PFS) 5.6 months and median overall survival (OS) 11.8 months. MYC was successfully evaluated in 298 cases and was amplified in 17 patients (5.7%). Individuals with MYC amplification showed a trend for a lower RR (7.7% versus 28.9%, p=0.12), shorter PFS (3.0 months versus 5.8 months, p=0.22) and shorter OS (11.3 months versus 12.6 months, p=0.15) than patients with non-amplified tumors. A Receiver Operating Characteristic (ROC) analysis was also performed in order to verify whether a better MYC GCN cut-off could discriminate between anti-EGFR sensitive and resistant cases. In this analysis, patients with mean MYC GCN ≥2.53 (N=199, 66.8%) had a significantly higher RR (32.2% versus 19.1%, p=0.02), a longer PFS (5.8 months versus 4.5 months, p=0.06) and a longer OS (12.3 months versus 11.4 months, p=0.59) than patients with mean GCN <2.53 (N=99, 33.2%). In order to assess the potential confounding effect of KRAS and BRAF status, we further analyzed the outcome of the 81 KRAS/BRAF wild-type patients according to MYC GCN. In this subset, a trend for improved RR (42% versus 20%, p=0.05), PFS (8.6 months versus 4.2 months, p=0.16) and OS (13.5 months versus 9.7 months, p=0.51) favored MYC FISH GCN ≥2.73 patients. Conclusions: MYC amplification is a rare event in mCRC, not significantly reducing sensitivity to anti-EGFR agents. A trend for better outcome was observed in presence of increased MYC GCN.

scholarly journals Targeted Elastin-like Fusion Proteins for Enhanced Imaging and Treatment of Non-Muscle Invasive Bladder Cancer

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Matthew L. Nordland ◽  
Craig J. Sweet ◽  
Mollie Shinkle ◽  
David H. Thompson
Keyword(s):  
Bladder Cancer ◽  
Fusion Proteins ◽  
Tumor Imaging ◽  
Tumor Resection ◽  
Performance Testing ◽  
The United States ◽  
Cancer Tissue ◽  
Treatment Technology ◽  
Protein Expression And Purification ◽  
Muscle Invasive

Background and Hypothesis: A recent study estimates 17,670 individuals will die from bladder cancer in the United States in 2019. With current imaging and treatment technology, bladder cancer is associated with high recurrence rates making it the highest lifetime treatment cost per patient. High expense is primarily due to the profound heterogeneity associated with bladder cancer necessitating repeated intervention. Traditional treatment of non-muscle invasive bladder (NMIBC) cancer following intravesical tumor resection often includes chemotherapy or immunostimulatory therapy via Bacillus Calmette-Guerin (BCG) infusions. Both lack specificity for cancerous tissue, leading to sub-optimal prognosis and unnecessary discomfort for patients. Furthermore, bladder cancer detection is limited in its precision. Methods such as CT/MRI urography and cystoscopies are unable to accurately detect tumors under 2 centimeters in diameter. Blue light cystoscopy, a gold standard detection method, is unable to accurately differentiate tumors from inflamed tissue. This leads to issues detecting aggressive carcinoma in situ. The goal of this project is to enhance tumor detection by fusing various targeting ligands to elastin-like peptides (ELP). Experimental Design or Project Methods: Using synthetic biology approaches, a library of ELP fusions were made and purified using a simplified organic extraction method. (Biomaterials Science 2018, 6 (4), 863-876) This resulted in exceptionally pure protein within a matter of hours. Contrast agents were covalently attached, and performance testing was done in murine bladder cancer cells. Results: Novel ELP fusions were successfully produced and sequences verified. Protein expression and purification yielded active targeted constructs which showed enhanced binding efficiency over non-targeted constructs. These ELP fusion proteins are effective transporters for rapid and preferential cargo entry into bladder cancer tissue. Conclusion and Potential Impact: Chemotherapeutic, immunostimulatory, and tumor imaging cargo are all bright candidates for targeted ELP fusion technology. Targeted ELP delivery may be a superior tool key to improving tumor visualization and treatment, leading to improved comfort and prognosis in patients with NMIBC.  

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