The majority of patients die from metastasis and not their primary tumor. Drugs targeting metastasis are therefore of increasing need. Crown Biosciences has validated a number of metastasis models, including spontaneous metastasis and experimental metastasis models. The models cover major cancer types such as breast, colon, liver, gastric, pancreatic, prostate, ovarian and melanoma.
Combination Chemotherapeutic Models
Crown has extensive experience in performing combination therapy studies using therapeutically relevant Standard of Cares for the appropriate cancer types. Our expert advice on appropriate models and optimum window of opportunity and combinations will help design an apppropriate study.
Matrigel plug assay with IHC analysis of blood vessels, as well as with hemoglobin concentration analysis, are both available for agents that may affect the angiogenesis process.
Dual Xenograft Models
With deep understanding of our models and large historical datasets, we have validated a series of pairs of models that may be put on the same mouse, without interfering with each other’s growth. The best use of those dual xenograft models is to demonstrate that the targeted agent is efficacious against one tumor but not the other, on the same mouse. In addition to that, in practice this modeling system saves significant amount of cost. We can then pass the resulting benefit to our clients.
Most xenograft models have very little stroma components, and even if some have, the stroma is from mouse rather than human. This is very different than what we see in human. It has been shown that admix stroma component with tumor cells in xenograft, such as fibroblast, mesenchymal stem cells, may not only change the tumor growth property, but may also change the drug response profile. This is especially true for many antibody therapeutics, where an ADCC effect may only be seen in tumors with human immune cells. We have validated systems where we can admix human PBMC with tumor cells to grow xenograft tumors in mice, and treatment with antibodies demonstrated significant ADCC effect in vivo. These and other MiXeno™ models may prove to be more relevant models in testing novel cancer therapeutic agents.
These unique models are derived from our HuPrime (patient derived xenograft, PDX) models. We created cell lines from HuPrime models, and inoculated mice with those cells to form xenograft tumors. Many of those cell lines harbor mutations of novel therapeutic targets, such as R-spondin (RSPO3), FLT3, ALK, and FGFR2. These PrimeXeno models are ideal models for early stage drug discovery, where a robust system is needed to screen for large number of compounds in an assay such as PK/PD analysis. They also complement the existing CDX models, where additional models for efficacy study are always appreciated.
Isogenic Xenograft Models
The explosion of knowledge regarding the genetic underpinnings of human cancer heralds a new era of targeted therapy. To date, in vivo cell based screening has proven a useful tool in almost all drug development programs. Cells used in such screens are usually harvested from cancer patients that harbor the specific mutation of interest, but these cells almost invariably contain many other additional mutations making it difficult to ascertain the specific functions of molecules being screened. Thus the lack of true control cells hampers the development of new cancer therapeutics.
Crown Biosciences has established a strategic partnership with Horizon Discovery, one of the leaders in isogenic cell lines. Using cell lines generated with Horizon Discovery’s proprietary rAAV-based GENESIS™ gene editing platform, we have established a comprehensive range of isogenic cancer models for our in vivo compound screening program to service our clients in academia and industry, with mutations in a wide variety of genes including KRAS, PIK3CA, PTEN, IDH1 and p53. These isogenic tumor models comprise pairs of cell lines which share the same genetic background, differing only by the mutation of interest and therefore allowing definitive studies of specific genetic variances to be performed. The same isogenic pairs of lines can be used for in vitro and in vivo experiments to ensure continuity and relevance of results. We have carried out intensive validation of these models in vivo to ensure the lines generate robust tumor growth in mice and the matched tumors differ only in the genetic composition of target gene.
Maximum Tolerated Dose Determinations
PK/PD Study: In Vivo Pharmacokinetic and Pharmacodynamic Studies
These are routinely performed in Crown, using western blot, IHC, ELISA, as well as FACS for PD analysis. Our DMPK group has state-of–the-art equipment and a comprehensive list of validated assays that can meet the highest quality standards.
Crown has one of the largest collections of xenograft tumor tissues. Those include both treatment naïve and SOC treated tissues, in frozen and FFPE format, ready for biomarker analysis. Premade or custom made tissue microarrays are also available.
In Vivo Imaging:
We have an in vivo imaging system that can perform X-ray imaging as well as bioluminescence, fluorescence imaging. The system allows longitudinal observations of the same tumor, particularly orthotopic tumors that are otherwise difficult to measure. In addition to that, metastasis imaging is also made available.
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