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14 pages, 2800 KiB

Open AccessArticle

Liquid Biopsy Landscape in Patients with Primary Upper Tract Urothelial Carcinoma

by Stephanie N. Shishido, Alireza Ghoreifi, Salmaan Sayeed, George Courcoubetis, Amy Huang, Brandon Ye, Sankalp Mrutyunjaya, Inderbir S. Gill, Peter Kuhn, Jeremy Mason and Hooman Djaladat

Cancers 2022, 14(12), 3007; https://doi.org/10.3390/cancers14123007 - 18 Jun 2022

Cited by 14 | Viewed by 3799

Abstract

Urothelial carcinomas (UCs) are a broad and heterogeneous group of malignancies, with the prevalence of upper tract urothelial carcinoma (UTUC) being rare, accounting for only 5–10% of total malignancies. There is a need for additional toolsets to assist the current clinical paradigm of [...] Read more.

Urothelial carcinomas (UCs) are a broad and heterogeneous group of malignancies, with the prevalence of upper tract urothelial carcinoma (UTUC) being rare, accounting for only 5–10% of total malignancies. There is a need for additional toolsets to assist the current clinical paradigm of care for patients with UTUC. As a non-invasive tool for the discovery of cancer-related biomarkers, the liquid biopsy has the potential to represent the complex process of tumorigenesis and metastasis. Herein, we show the efficacy of the liquid biopsy as a source of biomarkers for detecting UTUC. Using the third-generation high-definition single-cell assay (HDSCA3.0) workflow, we investigate liquid biopsy samples collected from patients with UTUC and normal donors (NDs) to provide critical information regarding the molecular and morphological characteristics of circulating rare events. We document several important findings from the liquid biopsy analysis of patients diagnosed with UTUC prior to surgery: (1) Large extracellular vesicles (LEVs) and circulating tumor cells (CTCs) are detectable in the peripheral blood. (2) The rare-event profile is highly heterogeneous. (3) Clinical data elements correlate with liquid biopsy analytes. Overall, this study provides evidence for the efficacy of the liquid biopsy in understanding the biology of UTUC with the future intent of informing clinical decision making, ultimately improving patient outcomes. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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17 pages, 3623 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Cellular and Acellular Analytes from Pre-Cystectomy Liquid Biopsies in Patients Newly Diagnosed with Primary Bladder Cancer

by Stephanie N. Shishido, Salmaan Sayeed, George Courcoubetis, Hooman Djaladat, Gus Miranda, Kenneth J. Pienta, Jorge Nieva, Donna E. Hansel, Mihir Desai, Inderbir S. Gill, Peter Kuhn and Jeremy Mason

Cancers 2022, 14(3), 758; https://doi.org/10.3390/cancers14030758 - 1 Feb 2022

Cited by 15 | Viewed by 4710

Abstract

Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other [...] Read more.

Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other treatments, is used to treat most BCa patients, as it offers the best chance of cure. However, even with curative intent, 29% of patients experience relapse of the cancer, 50% of which occur within the first year of surgery. This study aims to use the liquid biopsy to noninvasively detect disease and discover prognostic markers for disease progression. Using the third generation high-definition single cell assay (HDSCA3.0), 50 bladder cancer patient samples and 50 normal donor (ND) samples were analyzed for circulating rare events in the peripheral blood (PB), including circulating tumor cells (CTCs) and large extracellular vesicles (LEVs). Here, we show that (i) CTCs and LEVs are detected in the PB of BCa patients prior to cystectomy, (ii) there is a high heterogeneity of CTCs, and (iii) liquid biopsy analytes correlate with clinical data elements. We observed a significant difference in the incidence of rare cells and LEVs between BCa and ND samples (median of 74.61 cells/mL and 30.91 LEVs/mL vs. 34.46 cells/mL and 3.34 LEVs/mL, respectively). Furthermore, using classification models for the liquid biopsy data, we achieved a sensitivity of 78% and specificity of 92% for the identification of BCa patient samples. Taken together, these data support the clinical utility of the liquid biopsy in detecting BCa, as well as the potential for predicting cancer recurrence and survival post-cystectomy to better inform treatment decisions in BCa care. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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29 pages, 20760 KiB

Open AccessArticle

RalGPS2 Interacts with Akt and PDK1 Promoting Tunneling Nanotubes Formation in Bladder Cancer and Kidney Cells Microenvironment

by Alessia D’Aloia, Edoardo Arrigoni, Barbara Costa, Giovanna Berruti, Enzo Martegani, Elena Sacco and Michela Ceriani

Cancers 2021, 13(24), 6330; https://doi.org/10.3390/cancers13246330 - 16 Dec 2021

Cited by 19 | Viewed by 4555

Abstract

RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In [...] Read more.

RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In particular, TNTs are a novel mechanism of cell–cell communication in the tumor microenvironment, playing a central role in cancer progression and metastasis formation. However, the molecular mechanisms involved in TNTs formation still need to be fully elucidated. Here we demonstrate that mid and high-stage bladder cancer cell lines have functional TNTs, which can transfer mitochondria. Moreover, using confocal fluorescence time-lapse microscopy, we show in 5637 cells that TNTs mediate the trafficking of RalA protein and transmembrane MHC class III protein leukocyte-specific transcript 1 (LST1). Furthermore, we show that RalGPS2 is essential for nanotubes generation, and stress conditions boost its expression both in 5637 and HEK293 cell lines. Finally, we prove that RalGPS2 interacts with Akt and PDK1, in addition to LST1 and RalA, leading to the formation of a complex that promotes nanotubes formation. In conclusion, our findings suggest that in the tumor microenvironment, RalGPS2 orchestrates the assembly of multimolecular complexes that drive the formation of TNTs. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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15 pages, 3848 KiB

Open AccessArticle

Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

by Veronika Weyerer, Pamela L. Strissel, Reiner Strick, Danijel Sikic, Carol I. Geppert, Simone Bertz, Fabienne Lange, Helge Taubert, Sven Wach, Johannes Breyer, Christian Bolenz, Philipp Erben, Bernd J. Schmitz-Draeger, Bernd Wullich, Arndt Hartmann and Markus Eckstein

Cancers 2021, 13(10), 2327; https://doi.org/10.3390/cancers13102327 - 12 May 2021

Cited by 10 | Viewed by 2361

Abstract

Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) [...] Read more.

Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8⁺ scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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Review

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17 pages, 849 KiB

Open AccessReview

BCG in Bladder Cancer Immunotherapy

by Song Jiang and Gil Redelman-Sidi

Cancers 2022, 14(13), 3073; https://doi.org/10.3390/cancers14133073 - 23 Jun 2022

Cited by 52 | Viewed by 7599

Abstract

BCG is a live attenuated strain of Mycobacterium bovis that is primarily used as a vaccine against tuberculosis. In the past four decades, BCG has also been used for the treatment of non-muscle invasive bladder cancer (NMIBC). In patients with NMIBC, BCG reduces [...] Read more.

BCG is a live attenuated strain of Mycobacterium bovis that is primarily used as a vaccine against tuberculosis. In the past four decades, BCG has also been used for the treatment of non-muscle invasive bladder cancer (NMIBC). In patients with NMIBC, BCG reduces the risk of tumor recurrence and decreases the likelihood of progression to more invasive disease. Despite the long-term clinical experience with BCG, its mechanism of action is still being elucidated. Data from animal models and from human studies suggests that BCG activates both the innate and adaptive arms of the immune system eventually leading to tumor destruction. Herein, we review the current data regarding the mechanism of BCG and summarize the evidence for its clinical efficacy and recommended indications and clinical practice. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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24 pages, 755 KiB

Open AccessReview

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

by Jonathan Thomas and Guru Sonpavde

Cancers 2022, 14(7), 1795; https://doi.org/10.3390/cancers14071795 - 1 Apr 2022

Cited by 20 | Viewed by 4585

Abstract

Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding [...] Read more.

Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding of the somatic genetic aberrations potentially involved in its pathogenesis. Genetic alterations have been observed in kinases, such as FGFRs, ErbBs, PI3K/Akt/mTOR, and Ras-MAPK, and genetic alterations in critical cellular processes, such as chromatin remodeling, cell cycle regulation, and DNA damage repair. However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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25 pages, 1950 KiB

Open AccessReview

Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy

by Jianya Huan, Petros Grivas, Jasmine Birch and Donna E. Hansel

Cancers 2022, 14(6), 1555; https://doi.org/10.3390/cancers14061555 - 18 Mar 2022

Cited by 25 | Viewed by 4210

Abstract

The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR [...] Read more.

The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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12 pages, 891 KiB

Open AccessReview

Targetable Pathways in Advanced Bladder Cancer: FGFR Signaling

by Jin-Fen Xiao, Andrew W. Caliri, Jason E. Duex and Dan Theodorescu

Cancers 2021, 13(19), 4891; https://doi.org/10.3390/cancers13194891 - 29 Sep 2021

Cited by 31 | Viewed by 5403

Abstract

Bladder cancer is the 10th most commonly diagnosed cancer in the world, accounting for around 573,000 new cases and 213,000 deaths in 2020. The current standard treatment for locally advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. The significant progress [...] Read more.

Bladder cancer is the 10th most commonly diagnosed cancer in the world, accounting for around 573,000 new cases and 213,000 deaths in 2020. The current standard treatment for locally advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. The significant progress being made in the genomic and molecular understandings of bladder cancer has uncovered the genetic alterations and signaling pathways that drive bladder cancer progression. These developments have led to a dramatic increase in the evaluation of molecular agents targeting at these alterations. One example is Erdafitinib, a first-in-class FGFR inhibitor being approved as second-line treatment for locally advanced or metastatic urothelial carcinoma with FGFR mutations. Immunotherapy has also been approved as second-line treatment for advanced and metastatic bladder cancer. Preclinical studies suggest targeted therapy combined with immunotherapy has the potential to markedly improve patient outcome. Given the prevalence of FGFR alternations in bladder cancer, here we review recent preclinical and clinical studies on FGFR inhibitors and analyze possible drug resistance mechanisms to these agents. We also discuss FGFR inhibitors in combination with other therapies and its potential to improve outcome. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

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