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ORGANOID MODELS FOR CANCER DRUG DISCOVERY

For many decades, anti-cancer compounds and drugs have been screened for anti-cancer activities on human cancer cell lines cultured as suspensions or as adherent cell lines. This method is known as the 2D cell culture method. However, the results obtained from this method do not show translation to in vivo efficacy in animal models of cancer and in the clinic. The main reason for this is that the cancer cell lines grown in 2D culture do not recapitulate the complexity of tumors found in patients in terms of tumor architecture, tumor microenvironment, and the heterogeneity of genetic mutations.

The 3D Organoid model was developed to overcome the shortcomings of the 2D method. Here the cancer cells derived from human cancers are grown into organoids which have the characteristics of tumors in terms of architecture (histology) and genetic heterogeneity. They have been shown to maintain the characteristics of the tumor taken from the patient.

The patient derived organoids (PDOs) are valuable tools to evaluate the anti-cancer activity of clinical drug candidates in drug discovery programs in Cancer. The results obtained from the organoid screen are more predictive of efficacy in patients as they take into account the accessibility of drug to tumor cells across barriers and the heterogeneity of mutations.

Patient Derived Organoids (PDO) significantly improve the translational success for anti-cancer therapeutics in clinical trials.

1. Demonstration of Early Proof of Concept: Testing of Lead Compounds in PDOs expressing the pharmacological (drug) target help to establish proof of concept early in program and increase confidence for clinical efficacy. They also help in identification of Biomarkers for efficacy that can be applied in clinical trials.
2. Identification of target populations for Clinical Trials: At the nomination stage, Clinical Drug Candidates can be screened against a bank of PDOs, expressing the drug target, to identify specific patient molecular types in which they are maximally effective. This will enable selection of appropriate patients in clinical trials and increase the confidence for high clinical response.
3. Identification of Cancer Indications: Drug Candidates can be screened against PDOs from different cancers expressing the same abnormally expressed drug target to identify cancer indications for clinical trials.

TheraIndx has a library of Patient Derived Organoids (representing a range of cancers) with accompanying characterisation data (genotype, multi-omics, histopathology, cancer biology drug pathways).

These PDOs can be used for through the drug discovery and development process such as in

1. a) Screening compounds for Lead Identification and Lead Optimization
2. b) Candidate Drug Profiling
3. c) Identification of Patient populations in clinical trials.
4. d) Identification of biomarkers of efficacy in preclinical models for application in clinical trials.
5. e) Identification of appropriate drug combinations.

References:

• 1. Georgios Vlachogiannis et al., 2018. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018)


• 2. Margit Bleijs et al., 2019. Xenograft and organoid model systems in cancer research. The EMBO Journal (2019) 38: e101654


• Author : Ramesh Jayaraman-Chief Scientific Officer, TheraIndx Lifesciences.