Addressing Modern Diagnostic Pathology for Patient-Derived Soft Tissue Sarcosphere Models in the Era of Functional Precision Oncology.

Responses to therapy often cannot be exclusively predicted by molecular markers, thus evidencing a critical need to develop tools for better patient selection based on relations between tumor phenotype and genotype. Patient-derived cell models could help to better refine patient stratification procedures and lead to improved clinical management. So far, such ex vivo cell models have been used for addressing basic research questions and in preclinical studies. As they now enter the era of functional precision oncology, it is of utmost importance that they meet quality standards to fully represent the molecular and phenotypical architecture of patients' tumors. Well-characterized ex vivo models are imperative for rare cancer types with high patient heterogeneity and unknown driver mutations. Soft tissue sarcomas account for a very rare, heterogeneous group of malignancies that are challenging from a diagnostic standpoint and difficult to treat in a metastatic setting because of chemotherapy resistance and a lack of targeted treatment options. Functional drug screening in patient-derived cancer cell models is a more recent approach for discovering novel therapeutic candidate drugs. However, because of the rarity and heterogeneity of soft tissue sarcomas, the number of well-established and characterized sarcoma cell models is extremely limited. Within our hospital-based platform we establish high-fidelity patient-derived ex vivo cancer models from solid tumors for enabling functional precision oncology and addressing research questions to overcome this problem. We here present 5 novel, well-characterized, complex-karyotype ex vivo soft tissue sarcosphere models, which are effective tools to study molecular pathogenesis and identify the novel drug sensitivities of these genetically complex diseases. We addressed the quality standards that should be generally considered for the characterization of such ex vivo models. More broadly, we suggest a scalable platform to provide high-fidelity ex vivo models to the scientific community and enable functional precision oncology.

Functional Precision Oncology: The Next Frontier to Improve Glioblastoma Outcome?

Glioblastoma remains the most malignant and intrinsically resistant brain tumour in adults. Despite intensive research over the past few decades, through which numerous potentially druggable targets have been identified, virtually all clinical trials of the past 20 years have failed to improve the outcome for the vast majority of GBM patients. The observation that small subgroups of patients displayed a therapeutic response across several unsuccessful clinical trials suggests that the GBM patient population probably consists of multiple subgroups that probably all require a distinct therapeutic approach. Due to extensive inter- and intratumoral heterogeneity, assigning the right therapy to each patient remains a major challenge. Classically, bulk genetic profiling would be used to identify suitable therapies, although the success of this approach remains limited due to tumor heterogeneity and the absence of direct relationships between mutations and therapy responses in GBM. An attractive novel strategy aims at implementing methods for functional precision oncology, which refers to the evaluation of treatment efficacies and vulnerabilities of (ex vivo) living tumor cells in a highly personalized way. Such approaches are currently being implemented for other cancer types by providing rapid, translatable information to guide patient-tailored therapeutic selections. In this review, we discuss the current state of the art of transforming technologies, tools and challenges for functional precision oncology and how these could improve therapy selection for GBM patients.

A Case Study of a Rare Undifferentiated Spindle Cell Sarcoma of the Penis: Establishment and Characterization of Patient-Derived Models.

Rare sarcomas present significant treatment challenges compared to more prevalent soft tissue sarcomas due to limited treatment options and a poor understanding of their biology. This study investigates a unique case of penile sarcoma, providing a comprehensive morphological and molecular analysis. Through the creation of experimental patient-derived models-including patient-derived xenograft (PDX), 3D, and monolayer primary cultures-we successfully replicated crucial molecular traits observed in the patient's tumor, such as smooth muscle actin and CD99 expression, along with specific mutations in genes like TSC2 and FGFR4. These models are helpful in assessing the potential for an in-depth exploration of this tumor's biology. This comprehensive approach holds promise in identifying potential therapeutic avenues for managing this exceedingly rare soft tissue sarcoma.

Precision oncology: current and future platforms for treatment selection.

Genomic profiling of hundreds of cancer-associated genes is now a component of routine cancer care. DNA sequencing can identify mutations, mutational signatures, and structural alterations predictive of therapy response and assess for heritable cancer risk, but it has been less useful for identifying predictive biomarkers of sensitivity to cytotoxic chemotherapies, antibody drug conjugates, and immunotherapies. The clinical adoption of molecular profiling platforms such as RNA sequencing better suited to identifying those patients most likely to respond to immunotherapies and drug combinations will be critical to expanding the benefits of precision oncology. This review discusses the potential advantages of innovative molecular and functional profiling platforms designed to replace or complement targeted DNA sequencing and the major hurdles to their clinical adoption.

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models.

The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable tumor drivers and multidrug resistance. Novel personalized medicine approaches tailored to each tumor are urgently needed to improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling of tumor tissue identifies targets associated with clinical benefit in a subgroup of patients only and should be complemented with functional drug testing. In such an approach, patient-derived tumor cells are exposed to a library of approved oncological drugs in a physiological setting, e.g., in the form of animal avatars injected with patient tumor cells. We used molecularly fully characterized tumor samples from the INFORM study to compare drug screen results of individual patient-derived cell models in functional assays: (i) patient-derived spheroid cultures within a few days after tumor dissociation; (ii) tumor cells reisolated from the corresponding mouse PDX; (iii) corresponding long-term organoid-like cultures and (iv) drug evaluation with the corresponding zebrafish PDX (zPDX) model. Each model had its advantage and complemented the others for drug hit and drug combination selection. Our results provide evidence that in vivo zPDX drug screening is a promising add-on to current functional drug screening in precision medicine platforms.