PDXO Models

Background: Organoids

• Organoids are a type of 3D cell culture that closely resemble human organs in terms of histological features and are able to replicate their physiological functions in vitro. They are capable of undergoing self-proliferation, differentiation, self-renewal and self-assembly. Meantime, they also exhibit good genetic stability during long-term cultivation.
  Compared with conventional 2D tissue cultures, organoids represent an innovative technology which affords many advantages, like recapitulating cellular composition, 3D tissue architecture and physiological behavior of healthy and diseased organs of origin, good amenability for molecular and cellular characterization and manipulation as well as being suitable for high-throughput screening. Therefore, organoids are considered as an advanced in vitro tool for scrutinizing the physiological process of different organs or tissues of interest. On the other hand, relative to animal models, organoids offer simpler manipulation and can be used to investigate the mechanisms underlying disease occurrence and development. So far, organoids have been well-exploited in many areas, including drug discovery, safety and toxicity evaluation of drugs, translational precision medicine researches, mechanism studies on disease development, etc.

Advantages of PDXO Model

• PDXO is a PDX-derived in vitro 3D organoid model that inherits most advantages of PDX model. It can faithfully recapitulate the genomic, phenotypic and structural features of tumor tissue of patient origin. Therefore, it has been recognized as a good substitute to real patients and can provide accurate clinical response prediction.
• Advantages of PDXO model:
  PDXOs offer higher clinical relevance for drug response prediction. As the CSC-derived infinitestimal of human cancer tissue, the genomic, molecular biological and histo-pathological features are well recapitulated, and the architectures are also efficiently represented. By adopting a standardized cultivation system, PDXO provides an easily scalable in vitro system that is available for large-scale screenings and can produce high-quality read-outs with good repeatability and reproducibility, low batch-by-batch variation and high signal-to-noise ratio. The in vitro drug response results acquired using PDXO can accurately predict the in vivo tumor response using the PDX counterpart, therefore making PDXO a good in vitro validation tool for large-scale pre-screening of drug candidates before moving to the in vivo study. PDXO is amenable for molecular and cellular characterization and manipulation.

Applications of PDXO Model

• Drug pharmacology evaluation
  The major use of PDXO will be evaluation of drug efficacy for drug discovery and development. To make this happen, a bio-bank of PDXOs needs to be established. This bio-bank should cover all major cancer types and, under each cancer type, there should be multiple well-established PDXOs. In addition, each PDXO in the bio-bank should be well characterized and annotated (the same for the PDX counterparts), allowing us to extract their features and group them into different panels that can serve as representative surrogates for different cancer patient populations.
• Drug screening
  One application of PDXO is the large-scale drug screening prior to in vivo examination using the PDX model counterpart. As discussed above, PDXO recapitulates key features as PDX does and thus can predict the in vivo tumor response accurately. In vitro high-throughput screening using PDXOs offered an efficient way to assess the efficacy performance of a large amount of agents of interest in a short period of time. The results can not only be used to refine the agents for lead compound selection, but serve as a validation for the downstream in vivo study results as well.

Our Capabilities

• So far we have established 9 PDXO models, including 4 human colon cancer PDXOs, 1 pancreatic cancer PDXO, 2 gastric cancer PDXOs, 1 leukemia PDXO and 1 prostate cancer PDXO. We conducted bright field imaging analysis, H&E staining-based histological analysis and whole exome sequencing on each model, allowing us to extract and integrate the biological traits of each model for precision medicine research purpose. Meantime, we are capable of running drug screening on PDXOs using CTG (3D) assay as well as conduct different biological analysis and modification on PDXOs (e.g. viral transfection).

Case Study

• Take one human colon cancer PDXO as an example. The histological and genomic features of this PDXO are characterized using H&E staining and whole exome sequencing (WES). Typically, the comparison of WES results between PDXO and its matched PDX confirmed that PDXO preserves the tumor-associated mutations present in its PDX counterpart. We are also capable of running drug screening using Cell Titer Glo (CTG) 3D assay on PDXOs. Our preliminary data has confirmed that the in vitro drug response results from the PDXO are consistent with the in vivo ones using the matched PDX counterpart.
  

FAQ

• What is PDX Model?

  Patient-derived xenograft or PDX model is now recognized as the good in vivo model for predicting clinical outcomes. It is derived by growing a fragment of patient tumor tissue on immuno-deficient mice, which faithfully recapitulates the genomic, phenotypic and molecular biological complexities found in the cancer tissue of origin.

• What is PDXO Model?

  PDX-derived organoid or PDXO model is an in vitro model that inherits most of the advantages of PDX models. PDXO model can be established using the same protocol for patient-derived organoid or PDO model development with some adaptive modifications. PDXOs will be embedded in Matrigel for 3D culture and cultivated in growth medium that is enriched with a tailored cocktail of growth factors. Under such conditions, cancer stem cells or CSCs of cancer origin can retain their genomic, phenotypic and structural features while expansion.

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