Patient-Derived Renal Cell Cancer Organoids Promising to the Development of Personalized Therapy, Understanding Treatment Resistance

According to findings presented at the Society of Urologic Oncology 25^th Annual Meeting, implementing patient-derived organoids (PDOs) with multi-omics analysis can be instrumental in generating personalized treatments for renal cell carcinoma (RCC), recognizing drug response markers, and gaining insight into resistance mechanisms.

Daniel Triner, MD, PhD, Chief Urology Resident at the University of Michigan in Ann Arbor, and colleagues wrote, “Despite progress, the response rate of renal cell carcinoma to systemic therapy is ~30%. Hence, a critical need exists to develop novel therapeutic targets and personalized treatment strategies. Patient-derived organoids, a 3D ex-vivo model system that recapitulates the histological, genomic, and transcriptomic landscape of parental tumors, represents a novel platform for individual drug testing.”

To identify predictive markers of drug response, the researchers conducted integrative molecular profiling of patient-matched primary tumor tissue and RCC PDOs.

Researchers gathered and reviewed tissue samples from normal and two separate tumor areas (T1/T2) in patients with RCC who were undergoing radical nephrectomy. The samples included those from a metastasectomy of a peri-bronchial lymph node and a liver metastasis core needle biopsy, which were then molecularly profiled using bulk whole exome, whole transcriptome, and single-cell RNA sequencing (scRNAseq).

Patient-derived organoids (PDOs) were also generated to assess therapeutic responses to 26 clinically available drugs. Dose-response curves were evaluated from IC50 experiments, and scRNAseq analysis was performed pre- and post-drug exposure to gain better insight into both clinical response and resistance mechanisms.

The study cohort involved eight patients, including six with clear cell RCC, one with papillary RCC, and one diagnosed with chromophobe RCC. PDOs were successfully generated for nine normal and nine tumor samples.

Analysis of patient #5 with clear cell RCC exhibited a loss of chromosome 3p in both T1 and T2 samples. ScRNAseq revealed elevated levels of carbonic anhydrase IX(CA9), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR) gene expression, and two unique tumor cell sub-populations.

PDOs from patient #5 were sensitive to sunitinib (targeting VEGFA-VEGFR axis) and neratinib (targeting EGFR), and therapy with neratinib eradicated cluster-0 tumor cells but expanded cluster-13 cells, which exhibited elevated interferon (IFN) gamma and IFN alpha response pathway transcriptomic signatures.

Based on these findings, Dr. Triner and colleagues concluded, “Integration of PDOs, a clinically relevant 3D ex-vivo model system, with multi-omics, can enable data-driven development of personalized RCC therapies as well as insights into mechanisms of treatment resistance.”

Finally, the researchers noted that ongoing research would provide additional understanding of tumor heterogeneity, the mechanisms associated with tumor evolution, and related therapeutic resistance.

Reference

Triner D, Pham T, Knuth Z et al. Patient-Derived Renal Cell Cancer Organoids as a Model to Assess Therapeutic Targets and Treatment Resistance Mechanisms. Poster #53. Presented at the 25th Annual Meeting of the Society of Urologic Oncology; December 4-6, 2024; Dallas, Texas.