Prospective pharmacotyping of urothelial carcinoma organoids for drug sensitivity prediction – feasibility and real world experience
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ABSTRACT:
PROVIDER: PRJNA1180454 | ENA |
REPOSITORIES: ENA
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Project description:Urothelial carcinoma (UC) of the urinary bladder has significant challenges in treatment due to its diverse genetic landscape and variable response to systemic therapy. In recent years, patient-derived organoids (PDOs) emerged as a novel tool to model primary tumors with higher resemblance than conventional 2D cell culture approaches. However, the potential of organoids to predict therapy response in a clinical setting remains to be evaluated. This study explores the clinical feasibility of PDOs for pharmacotyping in UC. Initially, we subjected tumor tissue specimens from 50 patients undergoing transurethral resection or radical cystectomy to organoid propagation, of whom 19 (38%) yielded PDOs suitable for drug sensitivity assessment. Notably, whole transcriptome-based analysis indicated that PDOs may show phenotypes distinct from their parental tumor tissue. Pharmacotyping within a clinically relevant timeframe [mean of 35.44 and 55 days for non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), respectively] was achieved. Drug sensitivity analyses revealed marked differences between NMIBC and MIBC, with MIBC-derived organoids demonstrating higher chemosensitivity toward clinically relevant drugs. A case study correlating organoid response with patient treatment outcome illustrated the complexity of predicting chemotherapy efficacy, especially considering the rapid acquisition of drug resistance. We propose a workflow of prospective organoid-based pharmacotyping in UC, enabling further translational research and integration of this approach into clinical practice.
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Project description:Fibroblast Growth Factor Receptor 3 Alterations and Response to Immune Checkpoint Inhibition in Metastatic Urothelial Cancer: A Real World Experience
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Project description:Purpose: We evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance Methods: 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014-2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3 alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients Results: Our findings from this dataset confirm that FGFR3-altered (n=17) and wild type (n=86) bladder cancers are equally responsive to ICB (12 vs 19%, p=0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumors have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response Conclusions: Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumors have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.
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Project description:Urothelial cancer is a challenging disease with a wide tumor-biological spectrum. Most molecular classification attempts are transcriptome-based and relate only indirectly to the therapeutically relevant protein level. We improve preanalytical preparation of clinical samples for proteome analyses and characterize a comprehensive cohort of 434 samples with 242 tumors and 192 paired normal mucosae. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify five tumor clusters that add prognostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both, in silico as well as in vitro data, indicate predictive value of the proteomic clusters for these drugs. Comparative validation on external transcriptomic data confirms prognostic relevance and contextualizes proteomic and transcriptomic classifications. A real-world diagnostic approach based on immunohistochemistry further validates our proteomic data but underlines the necessity of omics scale molecular analyses for personalized oncology.
2024-06-16 | PXD041268 | Pride
Project description:Urothelial cancer is a challenging disease with a wide tumor-biological spec-trum. Most molecular classification attempts are transcriptome-based and re-late only indirectly to the therapeutically relevant protein level. We improve preanalytical preparation of clinical samples for proteome analyses and char-acterize a comprehensive cohort of 434 samples with 242 tumors and 192 paired normal mucosae. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify five tumor clusters that add prog-nostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both, in silico as well as in vitro data, indicate predictive value of the proteo-mic clusters for these drugs. Comparative validation on external transcriptom-ic data confirms prognostic relevance and contextualizes proteomic and tran-scriptomic classifications. A real-world diagnostic approach based on im-munohistochemistry further validates our proteomic data but underlines the necessity of omics scale molecular analyses for personalized oncology.
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Project description:The primary goals of this study are to: determine how intracellular infection of urothelial cells with uropathogenic Escherichia coli influences urothelial cell metabolism, and determine the influence of cytochrome bd on the urothelial cell response to infection
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Project description:Purpose: The goals of this study are to compare 1. The transcription profile in KDM6A wildtype and KDM6A mutated urothelial bladder carcinoma. 2. The transcriptional changes in KDM6A mutated urothelial bladder carcinoma upon EZH2 inhibitor treatment.
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Project description:Smoking is a major risk factor for Urothelial carcinoma (UC). However the complex mechanisms, how smoking promotes carcinogenesis and tumour progression, remain obscure. A microarray based approached was therefore performed to detect the smoking derived gene expression alteration in non-malignant and malignant urothelial tissues from patients with superficial or invasive UC. Smoking enhanced cell migration and response to tissue damages. In non-malignant tissues smoking induced immune response and altered the cytoskeleton. In urothelial carcinoma, smoking altered extracellular and chromosome structures. Smoking affected tissues from patients with invasive carcinomamore strongly, up-regulating particularly growth factors and oncogenes in non-malignant tissue of patients with invasive but not with superficial carcinoma. In former smokers, comparable changes were seen in tissues form patients with invasive disease while they were minor or reversed in tissue of patients with superficial disease. Best but not complete tissue repair was suggestedfor non-malignant tissue from patients with superficial tumours. we used microarray techniques to define gene expression profile which may explain the contribution of smoking to urothelial carcinoma. Gene expression profiling using GeneChip HG-U133A Plus 2.0 (Affymetrix) was performed on non-malignant and carcinogenic urothelium from six patients with superficial and six with invasive urothelial carcinoma, each group including two current, former, and non-smokers.
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