Supervisors: Dr. Thierry MASSFELDER & Dr. Véronique LINDNER
Overview
Patient-derived xenograft (PDX) models preserve tumor heterogeneity and are highly valuable for identifying predictive biomarkers of therapeutic response and resistance. However, the success rate for urological cancers is far from 100% and it takes up to 18 months to develop these models. This makes it difficult to provide patients with timely, tailored therapies. To address this challenge, our scientific project — launched in mid-2019 — aims to develop more suitable, complementary models to PDX. Specifically, we are working on creating 3D organoids and tumoroids for various cancer types, including but not limited to kidney cancer (KCa), bladder cancer (BCa) and prostate cancer (PCa), derived from cells and tumors.
Our approach considers tumor heterogeneity by developing 3D structures from different parts of the tumor, incorporating all subcellar populations (tumor, stromal and immune cells). We also use experimental approaches, currently more especially for KCa, allowing us to preserve this subcellular population. In addition, we aim to integrate microfluidic-based device to mimic vascularization and metastastic dissemination for drug testing (tumor organoid-on-a-chip, TOOC, platforms, such as Akita platform). We thus have innovative ideas for tools in this space. Ultimately, our goal is to establish an innovative platform combining both PDX and 3D models for translational and preclinical research, as well as personalized medicine.
Our project addresses the urgent need to develop more accurate tumor models for more effective and selective anti-cancer drug screening. We aim to provide a ready-to-use prototype of a next-generation drug screening platform to tackle a significant health challenge. Currently, 85% of new drugs fail in early clinical trials due to inefficacy. High attrition rates in cancer drug development often stem from a lack of sufficiently predictive preclinical screening tools to select potentially effective drug candidates. The added value lies in the microfluidic-based device, which closely mimics in vivo conditions and allows for the analysis of therapeutic responses including drug effects on metastatic potential of each tumor.
Innovative and emerging projects
Development of PDX models for urological cancers
Development of innovative 3D models for urological cancers, currently more especially for KCa and studies of the efficacy of standard and emerging therapies based on the molecular classification of tumors
Investigation of the therapeutic impact of prohibitins (PHBs) ligands in oncology, especially KCa
Molecular profiling of KCa using proteomic approaches
Inhibition of cellular metabolism through innovative nanoformulations (combination therapy) in PCa
Inhibition of cellular metabolism and ferroptosis through innovative nanoformulations (combination therapy) in KCa
Identification of resistance mechanisms to second-generation hormone therapy (abiraterone) in PCa
Key achievements (completed or ongoing)
Proteomic profiling of KCa (558 tumors across various subtypes) – Completed, submitted for publication
Characterization of a panel of PDX models for KCa, BCa and PCa – Completed and published
Identification of the role of vitamin D and calcium channels in PCa – Completed and published
Identification of resistance mechanisms to second-generation hormone therapy involving the PARP pathway (apoptosis, androgen receptor-independent) in PCa – Completed and published
Development of innovative 3D models (containing tumor cells, tumor fibroblasts, and autologous immune cells) for KCa, particularly clear cell renal cell carcinoma, the main KCa subtype – Ongoing
Prediction of response to adjuvant pembrolizumab for localized stages
Prediction of response to standard and emerging therapies based on tumor molecular classification according to the molecular classification of KCa based on RNA- and ATAC-seq analysis
Prediction of metastatic potential and of therapeutic influence on metastatic potential, according to the molecular classification of KCa based on RNA- and ATAC-seq analysis
Targeting cellular metabolism using nanoformulations combining siRNA and therapeutic molecules in PCa – Ongoing
Search for new therapeutic targets in KCa – Ongoing :
Project: Investigation of the oncogenicity of PHBs 1 and 2 to propose new therapeutic options based on their inhibition by their ligands
Goal: To determine whether this pathway is oncogenic in KCa through 2D/3D and in vivo studies with PHBs ligands
Preliminary results: Highly promising, with the identification of several ligands that inhibit up to 95% of cell viability in 2D/3D models
Targeting cellular metabolism and ferroptosis using nanoformulations combining siRNA and therapeutic molecules in KCa – Ongoing , search of financial supports