EAU 2020: The Future of Personalized Treatment: Test the Tumor for a Response

(UroToday.com) Dr. Michael Shen began his discussion on the use of organoid models for studying tumor evolution and drug response. The reasons he uses organoid models include:

  • A need for model systems that can capture tumor heterogeneity
  • Clonal evolution of tumors plays a key role in drug resistance
  • Drug responses are readily assayed in organoid culture
  • Patient-derived organoid models are amenable for genetic manipulation
  • Bladder cancer readily allows sampling of recurrent disease

The entire process or isolation and analysis of human bladder organoids was described next, as shown in Figure 1. The efficiency of orthotopic xenografting is 83%.

Figure 1 – Isolation and analysis of human bladder organoids:


Dr. Shen performed targeted sequencing of the organoids, and their corresponding parental tumors and normal blood. This has revealed that the organoids are highly concordant with their parental tumors (figure 2), which implies that much of the tumor heterogeneity found in the parental tumor was also present in the organoid lines. The targeted sequencing also revealed that the organoid lines as a whole, capture much of the mutational spectrum of human bladder cancer (Figure 3).

Figure 2 – Sequencing or organoids, parental tumor, and normal blood:


Figure 3 – Genomic analysis of bladder organoids:


It is possible to use these organoid lines to survey drug responses to a range of different compounds. There is a correlation between increased drug resistance with tumor stage and recurrence.

It is possible to establish organoid lines from patients with recurrent disease, both pre- and post-treatment. When looking at the drug response of organoid pairs from the same patient that was only surgically treated, it is seen that the organoid pair lines manifest similar responses to a variety of compounds. In contrast, the pair of organoid lines from a patient that was treated with mitomycin C and BCG show that the recurrent line is much more resistant to a range of different compounds, but not to others.

In recent unpublished work done by Dr. Shen, his team had focused on the response to cisplatin, which is part of the standard of care in patients with muscle-invasive bladder cancer. Dr. Shen examined whether the response to cisplatin in the different organoid lines correlates to the presence of mutations in ERCC2, which is a component of the nucleotide excision repair pathway. Previous studies have shown that ERCC2 mutations correlate with cisplatin sensitivity.

There is a significant percentage of patients with MIBC who display a complete pathologic response after neoadjuvant cisplatin-based chemotherapy. In a cohort of these patients who displayed complete pathologic response after neoadjuvant chemotherapy, that elected not to undergo radical cystectomy, but instead underwent active surveillance, nearly half of these patients displayed a long-term durable response. Therefore, Dr. Shen hopes that he would be able to establish organoid lines from patients in future cohorts who will have complete pathological response following neoadjuvant chemotherapy alone, and this will allow him to investigate the mechanism behind this long-term durable response that was observed after treatment with neoadjuvant chemotherapy alone.

In the next part of this talk, Dr. Shen discussed the topic of tumor plasticity, which also correlates with drug response and patients’ outcomes. It has been shown that many of the organoid lines demonstrate phenotypic instability. They have a plasticity that corresponds to a luminal to basal transition. This means that they start out demonstrating a luminal phenotype, but in the culture, they acquire a basal phenotype, which interestingly, in most cases, is reverted in orthotopic xenografts, indicating that there is a potential role for the stromal microenvironment in suppressing the formation of a basal phenotype. Dr. Shen believes that the basis for this plasticity is epigenetic. He managed to show that there are distinct patterns of chromatin accessibility in the plastic lines, with plastic lines showing partially open chromatin at luminal markers. This means that the plastic lines have an epigenetic memory of their luminal origins.

In summary, organoid assays can be readily used to assess drug response. Cisplatin response is only partially correlated with DNA damage response (DDR) mutations, and cellular plasticity in culture may reflect processes of disease progression in vivo.  Lastly, organoid models allow mechanistic studies of complex questions in cancer biology.

Presented by: Michael Shen, MD, Columbia University Medical Center, NY, USA

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020