Browsing by Subject "Bladder cancer"
Now showing 1 - 10 of 20
Results Per Page
Sort Options
Item A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera(Wiley, 2020) Jack, Sherwin; Madhivanan, Kayalvizhi; Ramadesika, Swetha; Subramanian, Sneha; Edwards, Daniel F., II; Elzey, Bennett D.; Dhawan, Deepika; McCluskey, Andrew; Kischuk, Erin M.; Loftis, Alexander R.; Truex, Nicholas; Santos, Michael; Lu, Mike; Rabideau, Amy; Pentelute, Bradley; Collier, John; Kaimakliotis, Hristos; Koch, Michael; Ratliff, Timothy L.; Knapp, Deborah W.; Aguilar, Ruben C.; Urology, School of MedicineBladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF–anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.Item Accurate Documentation Contributes to Guideline-concordant Surveillance of Non-Muscle Invasive Bladder Cancer: a Multi-site VA Study(Elsevier, 2023) Lyall, Vikram; Ould Ismail, A. Aziz; Haggstrom, David A.; Issa, Muta M.; Siddiqui, M. Minhaj; Tosoian, Jeffrey; Schroeck, Florian R.; Medicine, School of MedicineObjective: To determine if accurate documentation of bladder cancer risk was associated with a clinician surveillance recommendation that is concordant with AUA guidelines among patients with nonmuscle invasive bladder cancer (NMIBC). Methods: We prospectively collected data from cystoscopy encounter notes from four Department of Veterans Affairs (VA) sites to ascertain whether they included accurate documentation of bladder cancer risk and a recommendation for a guideline-concordant surveillance interval. Accurate documentation was a clinician-recorded risk classification matching a gold standard assigned by the research team. Clinician recommendations were guideline-concordant if the clinician recorded a surveillance interval that was in line with the AUA guideline. Results: Among 296 encounters, 75 were for low-, 98 for intermediate-, and 123 for high-risk NMIBC. 52% of encounters had accurate documentation of NMIBC risk. Accurate documentation of risk was less common among encounters for low-risk bladder cancer (36% vs 52% for intermediate- and 62% for high-risk, P < .05). Guideline-concordant surveillance recommendations were also less common in patients with low-risk bladder cancer (67% vs 89% for intermediate- and 94% for high-risk, P < .05). Accurate documentation was associated with a 29% and 15% increase in guideline-concordant surveillance recommendations for low- and intermediate-risk disease, respectively (P < .05). Conclusion: Accurate risk documentation was associated with more guideline-concordant surveillance recommendations among low- and intermediate-risk patients. Implementation strategies facilitating assessment and documentation of risk may be useful to reduce overuse of surveillance in this group and to prevent unnecessary cost, anxiety, and procedural harms.Item Analysis of the cytotoxic activity of carboplatin and gemcitabine combination(The International Institute of Anticancer Research, 2010-11) Wang, Sisi; Zhang, Hongyong; Evans, Christopher; Pan, Chong-Xian; Department of Pathology and Laboratory Medicine, IU School of MedicineAim To determine if the drug doses and administration schedules of carboplatin and gemcitabine combination affect antitumor effects. Materials and Methods The inhibition of cell viability was measured by MTT assay. Median effect analysis was conducted to determine the cytotoxicity activity of carboplatin and gemcitabine combination. Cell cycle changes were analyzed by flow cytometry. Results Synergism was observed when the bladder cancer cell line 5637 cells were treated with gemcitabine followed by carboplatin or concurrent carboplatin/gemcitabine. In contrast, moderate antagonism was observed when cells were treated with carboplatin followed by gemcitabine. Cell cycle analysis showed that the combined effect of these two drugs was cell cycle disturbance. Conclusions Different doses and administration schedules affect the anti-tumor effect of carboplatin/gemcitabine combination that may have clinical significance in the treatment for bladder cancer.Item Anti-tumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer(American Association for Cancer Research, 2019-08-14) Fishel, Melissa L.; Xia, Hanyu; McGeown, Jack; McIlwain, David W.; Elbanna, May; Craft, Ariel A.; Kaimakliotis, Hristos Z.; Sandusky, George E.; Zhang, Chi; Pili, Roberto; Kelley, Mark R.; Jerde, Travis J.; Pharmacology and Toxicology, School of MedicineBladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.Item Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy(MDPI, 2024-12-03) Eljilany, Islam; Coleman, Sam; Tan, Aik Choon; McCarter, Martin D.; Carpten, John; Colman, Howard; Naqash, Abdul Rafeh; Puzanov, Igor; Arnold, Susanne M.; Churchman, Michelle L.; Spakowicz, Daniel; Salhia, Bodour; Marin, Julian; Ganesan, Shridar; Ratan, Aakrosh; Shriver, Craig; Hwu, Patrick; Dalton, William S.; Weiner, George J.; Conejo-Garcia, Jose R.; Rodriguez, Paulo; Tarhini, Ahmad A.; Medicine, School of MedicineBackground: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. Methods: We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar® project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. Results: In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly (p = 4.67 × 10-12 and p = 5.80 × 10-12, respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic (p = 2.23 × 10-8, 3.86 × 10-28, and 7.85 × 10-9, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma (p = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61-0.64). Conclusions: Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival.Item Editorial: Emerging Biomarkers in Genitourinary Tumors(Frontiers, 2019-04-26) Montironi, Rodolfo; Santoni, Matteo; Cimadamore, Alessia; Lopez-Beltran, Antonio; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineItem Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)(BMC, 2021-05-24) Grivas, P.; Loriot, Y.; Morales-Barrera, R.; Teo, M. Y.; Zakharia, Y.; Feyerabend, S.; Vogelzang, N.J.; Grande, E.; Adra, N.; Necchi, A.; Rodriguez-Vida, A.; Gupta, S.; Josephs, D.H.; Srinivas, S.; Wride, K.; Thomas, D.; Simmons, A.; Loehr, A.; Dusek, R.L.; Nepert, D.; Chowdhury, S.; Medicine, School of MedicineBackground: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.Item Enhancing immune checkpoint blockade therapy of genitourinary malignancies by co-targeting PMN-MDSCs(Elsevier, 2022) Lu, Xuemin; Lu, Xin; Medicine, School of MedicineImmune checkpoint blockade (ICB) as a powerful immunotherapy has transformed cancer treatment. The application of ICB to genitourinary malignancies has generated substantial clinical benefits for patients with advanced kidney cancer or bladder cancer, yet very limited response to ICB therapy was observed from metastatic castration-resistant prostate cancer. The efficacy of ICB in rare genitourinary tumors (e.g. penile cancer) awaits results from ongoing clinical trials. A potential barrier for ICB is tumor-infiltrating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) with their functions and mechanisms recently revealed. Preclinical studies suggest that successful therapeutic inhibition of PMN-MDSCs synergizes effectively with ICB to eradicate ICB-refractory genitourinary malignancies.Item Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer(MDPI, 2021-01-03) Lopez-Beltran, Antonio; Cimadamore, Alessia; Blanca, Ana; Massari, Francesco; Vau, Nuno; Scarpelli, Marina; Cheng, Liang; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineA number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.Item Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis(MDPI, 2021-11-01) Lopez-Beltran, Antonio; Blanca, Ana; Cimadamore, Alessia; Gogna, Rajan; Montironi, Rodolfo; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineMolecular classification of bladder carcinoma is a relevant topic in modern bladder cancer oncology due to its potential to improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation of molecular classification in practice is typically limited due to the high complexity of the required technology, the elevated costs, and the limited availability of this technology worldwide. We have conducted a gene expression analysis using a four-gene panel related to luminal and basal subtypes in a series of 91 bladder cancer cases. NanoString-based gene expression analysis using typically luminal (GATA3+/KRT20+) and basal markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial bladder carcinoma samples as luminal, basal, and a third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three categories were meaningful in terms of overall cancer-specific survival (p < 0.0001) or when classified as conventional urothelial carcinoma and variant histology urothelial carcinoma (p < 0.0001), NMIBC vs. MIBC (p < 0.001), or by AJCC stage category Ta (p = 0.0012) and T1 (p < 0.0001) but did not reach significance in T2-T4 (p = 0.563). PD-L1 expression (low vs. high) was also different according to molecular subtype, with high PD-L1 expression mostly seen in basal and null subtypes and carcinomas with variant histology (p = 0.002). Additionally, the luminal subtype was enriched in NMIBC with favorable cancer-specific survival (p < 0.0001). In contrast, basal and null subtypes resulted in aggressive MIBC tumors with shorter cancer-specific survival (p < 0.0001), some of which presented variant histology. In conclusion, a comprehensive evaluation of a gene classifier related to molecular taxonomy using NanoString technology is feasible. Therefore, it might represent an accessible and affordable tool in this rapidly expanding area of precision genomics.