Translation: Translation using patient-derived organoids

Employing patient-derived organoids as a translational validation platform

As patient-derived organoids (PDOs) recapitulate key characteristics of the parental tumor remarkably, this technology represents a major engine of forward and reverse translation in oncology. In order to close the gap between classic in vitro assays, animal model systems, and clinical applications, PDOs are extremely valuable for validation purposes. For example, we were able to underscore the importance of a novel β2 adrenergic-neurotrophin feed-forward loop in PDAC. To our surprise, treatment with propranolol affected PDO viability significantly and further augmented the effects of the chemotherapeutic agent gemcitabine (Renz et al., Cancer Cell 2018). Another exciting therapeutic avenue we were able to support with our PDO models, is based on the observation that mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase (Ruess et al., Nature Medicine 2018). Importantly, discoveries from these mechanistic studies already led to an international phase I/Ib trial funded by AACR/Lustgarten/Stand Up To Cancer (SHERPA trial). Besides these tumor-cell intrinsic approaches, we have employed PDO technology in a collaborative effort to test the effectiveness of CAR-T cell therapy (Lesch et al., Nature Biomedical Engineering 2021). These findings underscore the applicability of PDO technology as a modular system together with other cell types such as immune cells or CAFs (Feldmann et al., Gastroenterology 2021).

Cell-free DNA in PDO supernatant recapitulates patient tumor genomics

One of the major challenges in using PDOs in precision oncology is the time from biopsy to functional characterization. This is particularly true for biopsy specimens with limited tumor cell yield, a typical characteristic of biopsies from endoscopic ultrasound-guided fine needle aspirations (EUS-FNAs). To accelerate genetic characterization as well as subsequent functional testing of PDOs, both required for clinical implementation, we tested conditioned media of individual PDOs for cell-free tumor DNA (cfDNA) to detect driver mutations already early on during the expansion process. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72 hours after the biopsy, recapitulate the mutational profile of the primary tumor. In addition, we demonstrate that this workflow is feasible even in patients of whom the amount of tumor material was not sufficient for molecular characterization by classical tumor tissue profiling. Our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach, this can be achieved rapidly and feasibly with broad implications in clinical practice (Dantes,…, Reichert, JCI Insight 2020).

Implementation of a functional precision oncology platform

Despite the success of precision oncology, the frequency of molecular-informed therapy decisions in PDAC is low. Primary PDAC models, such as PDOs, allow to implement a mechanistic layer into precision oncology by using them in genetic or pharmacological screening experiments. We developed a longitudinal precision oncology platform based on functional model systems to identify chemotherapy-induced vulnerabilities. We demonstrate that treatment-induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker. This is remarkable as it indicates that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer (Peschke et al., EMBO Mol Med 2022).