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Colorectal Cancer Mouse Tumor Organoids as Pre-clinical Models for Therapeutical Testing

Periodic Reporting for period 1 - CRC-MTOs (Colorectal Cancer Mouse Tumor Organoids as Pre-clinical Models for Therapeutical Testing)

Reporting period: 2018-12-01 to 2020-05-31

Colorectal cancer (CRC) is one of the most prevalent malignancies in the world, causing around 700.000 deaths worldwide every year. Metastatic spread of the disease is the leading cause of death by this type of cancer. Our lab generated a unique model to study metastatic CRC in immunocompetent mice based on organoid technology. This model allows pre-clinical testing of immunotherapies and combinations with other compounds. As proof of concept we showed that elevated TGF-beta signaling in the tumor microenvironment operates as the main mechanism of immune evasion during metastasis formation in CRC (Tauriello et al., 2018). Treatment of mice bearing overt metastatic disease with anti-PD-1/PD-L1 immunotherapy alone had a minor therapeutic effect. However, combined anti-PD-L1 treatment with Galunisertib, a TGFBR1 inhibitor currently being tested in clinical trials for other malignancies, induced a pronounced immune response, which eradicated most metastases and prolonged recurrence-free survival for over a year after treatment cessation (Tauriello et al., 2018). Despite the utility of this model it could not be transferred to industry due to limitations associated to the use of mutant alleles that belong to several institutions and other restrictions.
The objective of this project was to create an equivalent collection of organoids carrying combinations of driver mutations in CRC amenable for licensing to private enterprises. Using CRISPR/Cas9 gene editing techniques, we have generated a new collection that opens up the possibility of establishing agreements with companies to improve the development of drugs for CRC and /or sponsored research. The commercial interest of these organoids is to offer pharmaceutical companies licensing our technology a competitive advantage in front of their competitors, being able to test their drug candidates in the closest model to the human being, prior to entering into clinical phases.