New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract.

Study Overview
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Brief Summary
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Upper Urinary Tract Urothelial Carcinomas are rare, aggressive tumors, accounting for 5 to 10% of all urothelial tumors. These include tumors which develop in the renal cavities (renal pelvis, calices) and ureteral tumors. Nephro-ureterectomy is the standard treatment but 80% of patients will have a relapse within 2 years. Only one trial has (Birtle et al. 2020), has shown the interest of postoperative chemotherapy. Neoadjuvant systemic treatment seems particularly interesting for a population which is going to undergo a nephronic loss and therefore reduction in kidney function which is likely to make patients ineligible for cisplatin. In favor of additional immunotherapy, it has been described that upper excretory tract tumors have a high immunogenic potential with a high rate of microsatellite instability. From surgical samples of patient tumors obtained after nephroureterectomy or biopsy material collected before treatment, we are going to generate patient-derived cell lines and xenograft models in the mouse. A recent publication has demonstrated the feasibility of this approach by specifying that the capture rate of tumor cells is 50% for patient-derived xenografts and 25% for patient-derived cells (Coleman et al. 2020). As tumors harvested from biopsies do not grow in patient-derived xenografts,we plan to graft the biopsies onto chorioallantoic chicken embryo membranes, a model which has never been used for this indication and which is one of the original features of our approach. These three concomitant approaches will allow us to increase our chances of obtaining stable upper urinary tract urothelial carcinoma lines to be used for the screening and identification of new treatments or new combinations of molecules that would benefit patients with upper urinary tract urothelial carcinomas, knowing that very few studies dedicated to this type of cancer have been conducted or published due to the rarity of the disease and the lack of existing models published on the subject of these particular tumors. .

Official Title
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Development of New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract.

Conditions
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Upper Urinary Tract Urothelial Carcinoma, Nephroureterectomy, Tumor, Xenograft Model

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients treated consecutively at the Urology Andrology Department of Nîmes University Hospital for high grade carcinoma of the pelvis or renal ureter with an indication for total nephroureterectomy decided during a multidisciplinary meeting. Patient with a diagnosis of high-grade urothelial carcinoma of the pelvis or renal ureter confirmed by histology (biopsy, biopsy of the ureteroscopic) or by cytology with the presence of : High-grade disease on ureteroscopic biopsy OR ; High grade disease on urinary cytology AND infiltrating appearance of the renal pelvic wall / ureter on the scanner (the presence of hydronephrosis will be considered as pervasive by definition) with a negative cytoscopy. Exclusion Criteria: Any patient who has undergone previous systemic treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological characteristics of patient-derived xenograft models after staining. | Microscopic observation of cells after staining with hematoxylin and eosin | 1-6 months after harvesting | 
| Study of genomes of tumor specimens | Exome sequencing of DNA cells isolated from original patient tumor specimens. | 1-6 months after harvesting | 
| Alterations in the genomes of patient-derived xenograft tumor models | Exome sequencing of DNA cells isolated from patient-derived xenograft tumor models. | 1-6 months after harvesting | 
| Alterations in the genomes of patient-derived cell line models | Exome sequencing of DNA cells isolated from patient-derived cell line models. | 1-6 months after harvesting | 
| Study of the transcriptome of patient tumor specimens. | RNA-sequencing of cells isolated from patient tumor specimens. | 1-6 months after harvesting | 
| Transcriptome of the patient-derived xenograft tumor models. | RNA-sequencing of cells isolated from patient-derived xenograft tumor models. | 1-6 months after harvesting | 
| Transcriptome of the patient-derived cell line models. | RNA-sequencing of cells isolated from patient-derived cell line models. | 1-6 months after harvesting | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity to Cisplatin: patient-derived cell line models | The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Cisplatin. | 6-8 months after harvesting | 
| Sensitivity to Carboplatin: patient-derived cell line models | The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Carboplatin. | 6-8 months after harvesting | 
| Sensitivity to Oxaliplatin: patient-derived cell line models | The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Oxaliplatin. | 6-8 months after harvesting | 
| Sensitivity to Gemcitabin: patient-derived cell line models | The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Gemcitabin. | 6-8 months after harvesting | 
| Tumor size in non-treated patient-derived xenograft models | The volume of tumors will be measured in mm3. | 1-6 months after harvesting | 
| Sensitivity to Cisplatin: tumor size in treated patient-derived xenograft models | To test the tumor cells' response to Cisplatin in xenograft models, the volume of tumors will be measured in mm3 and compared with the volume of tumors in the non-treated control group. | 6-8 months after harvesting | 
| Sensitivity to Cisplatin: tumor growth rate in patient-derived xenograft models | To test the tumor cells' response to Cisplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used. | 6-8 months after harvesting | 
| Sensitivity to Carboplatin: tumor size in treated patient-derived xenograft models | To test the tumor cells' response to Carboplatin in xenograft models, the volume of tumors will be measured in mm3 and compared with the volume of tumors in the non-treated control group. | 6-8 months after harvesting | 
| Sensitivity to Carboplatin: tumor growth rate in treated patient-derived xenograft models | To test the tumor cells' response to Carboplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used. | 6-8 months after harvesting | 
| Sensitivity to Oxiplatin: tumor size in treated patient-derived xenograft models | To test the tumor cells' response to Oxiplatin in xenograft models, the volume of tumors will be measured in mm and compared with the volume of tumors in the non-treated control group. | 6-8 months after harvesting | 
| Sensitivity to Oxiplatin: tumor growth rate in treated patient-derived xenograft models | To test the tumor cells' response to Oxiplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used. | 6-8 months after harvesting | 
| Sensitivity to Gemcitabine: tumor size in treated patient-derived xenograft models | To test the tumor cells' response to Gemcitabine in xenograft models, the tumor volume will be measured in mm3 and compared with the volume of tumors in the non-treated control group. | 6-8 months after harvesting | 
| Sensitivity to Gemcitabin: tumor growth rate in treated patient-derived xenograft models | To test the tumor cells' response to Gemcitabin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used. | 6-8 months after harvesting |