Understanding and overcoming cancer therapy resistance is a major overarching goal of our precision oncology program at the University of Bern. One of the greatest hurdles is the lack of reliable model systems to untangle resistance on a patient to patient basis. Animal models have been widely used to test highly focused questions in oncology and tumor resistance. However, to answer specific questions on a patient-specific basis animal models are not ideal, mostly because experiments are time consuming and incompatible with high-throughput screening.
Instead, we will harness the power of the patients' own tumors to study their disease. We propose using patient-derived cancer organoids (PDOs) from bladder and prostate cancer patients, referred to as genitourinary (GU) cancers, as an exemplar of common cancers prone to therapy resistance and progression.
PDOs are small 3-dimensional multicellular structures that can be used to study individual mechanisms of tumor formation and drug response. Unfortunately, the majority of PDOs cannot be maintained for long periods of time, limiting their use for research. The major focus of this proposal will be to test and compare different protocols currently in use to see which ones achieve consistent, reproducible, robust PDOs for every patient. These will allow optimized and standardizing procedures to study each patient's therapy response.
We will validate the growth conditions, run extensive genomic and functional characterization of the PDOs, and generate a fully annotated organoid biobank with clinically relevant information to quickly uncover the molecular aspects of tumor formation and the availability of new treatment options. The establishment of a reliable PDO program will positively impact the way we study tumor resistance while simultaneously decreasing the reliance on animal models.
“In our precision oncology program, we want to understand why some patients will not respond to a certain cancer therapy. This therapy resistance and patient diversity cannot easily be mimicked in cell lines and in animal models. Furthermore, to answer specific questions for patient care, we need to find alternatives that allow high throughput studies,” explains Kruithof-de Julio. “I believe that this project will change the way we study tumour resistance, replacing animal models where they do not add to solving one of the biggest current hurdles in cancer therapy.”
Dr Marianna Kruithof-de Julio
Prof. Mark Rubin
Department for BioMedical Research (DBMR), University of Bern