Custom Murine Tumor Homografts for Efficacy Assessment
by Jody Barbeau PhD, July 3, 2018 at 12:00 PM
Murine tumor homografts provide an immunotherapeutic efficacy testing platform with the strengths of GEMM paired with the operational simplicity of syngeneic tumor models. Here we discuss how these models are useful to fill in the gaps of available immuno-oncology models and as a more translational preclinical pharmacology model.
Syngeneics: Common Choice with Limited Cancer Types
Syngeneic models are usually the first choice for preclinical efficacy testing and studying mechanisms of action for surrogate and cross reactive immunotherapeutics. These immunocompetent models are simple and rapid to establish, with synchronized tumor development, providing a robust platform for novel immunotherapy evaluation.
However, there are limited numbers of syngeneic models available, and not all cancer types are covered. As they are derived from immortalized cancer cell lines that have been passaged in vitro, you might also see genetic drift from the original disease, or maybe a specific mutation/fusion of human disease is not expressed.
So, what do you do if there isn’t an obvious syngeneic model available for your cancer type of interest or molecular target? You could move to GEMM (genetically engineered mouse models). GEMM were developed to provide a better model of human cancer – specially designed around the genetic events observed in human disease, with transgenic, knock in, or knockout models based around oncogenes or tumor suppressors. A wide range of well-characterized models are available, with a clear molecular pathogenesis of disease.
GEMM: Not Suited for Efficacy Studies
If you are studying mechanisms of tumorigenesis or validating the function of a specific target, then GEMM is the right path to take. But if you’re looking to evaluate efficacy, you hit more stumbling blocks.
GEMM aren’t great for in vivo pharmacology studies for a number of reasons, based around the spontaneous nature of their tumors. These factors include:
- Long latency periods before tumor development, sometimes up to one year in length, requiring large cohorts, long breeding/study times, rolling enrollment, and difficulties in estimating treatment duration and determining readouts.
- Non-synchronized tumor development and disease progression within the cohort.
- 100% penetrance not being achieved.
These factors add up to a platform which is not robust enough for thorough preclinical decision making, with added potential for non-reproducible study data. What is needed is a platform that can combine the strengths of GEMM, but which can be used similarly to syngeneics, and which can fill in the gaps of currently missing immuno-oncology models.
Murine tumor homografts fulfil this need.
Homografts Industrialize the GEMM Tumor System
Murine tumor homografts essentially industrialize GEMM to provide a robust in vivo pharmacology model system, including specific cancer types and targets which are missing from syngeneic collections.
Murine tumor homograft models are developed from GEMM and carcinogen-induced tumors, with homografts engrafted in mice from the same strain. The tumors aren’t adapted to in vitro growth and mirror the original tumor histopathology and genetic profile. This means that collections of murine tumor homograft models include various differentiation phenotypes and clinically relevant disease pathways with oncogenic drivers. Essentially, murine tumor homograft models cover a wide range of cancer types and targets that aren’t found within limited syngeneic panels.
These models can then be utilized in a similar way to syngeneics, with cohorts of models used for large-scale, highly-reproducible efficacy studies. Tumor growth synchronization for these models is easily achievable, supporting robust efficacy studies combining GEMM and syngeneic advantages.
Custom Homograft Models for Unmet Needs
Murine tumor homografts are already being used in areas of high unmet need, such as pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by high levels of KRAS mutation, often combined with p53 mutation, and poor response to standard of care therapies. Single-agent immunotherapies have also proven clinically ineffective, and combination immunotherapy requires further study. Suitable, immunocompetent preclinical models which recapitulate the disease are needed to make further progress.
The Pan02 syngeneic model of PDAC is available, but this lacks strong clinical significance due to absence of the mutational spectrum when compared to clinical patients. A KPC GEMM is available, which incorporates mutations in the oncogenic KRAS and tumor suppressor Trp53. This model recapitulates the development of PDAC and along with other GEMM has been pivotal in PDAC preclinical research. But, as a GEMM, this is not a great efficacy testing platform.
A murine tumor homograft PDAC model has therefore been developed from the KPC GEMM. The model retains morphological similarity to the GEMM and human PDAC, the key driver mutations found in the parental GEMM, and a lack of response to standard of care and single agent immunotherapies.
Moving forward, the model is being used for robust combination immunotherapy efficacy and proof of concept studies, which can include specific targeted agents as needed.
Improved Translational Relevance
As well as providing niche models missing from syngeneic panels, murine tumor homografts also improve the translational relevance of your work. Murine tumor homografts conserve original murine tumor histo- and molecular pathology, with more structure and heterogeneity of tumors than syngeneic models and relevant tumor stroma.
Murine tumor homograft models also offer a lower tumor mutational load than syngeneics, which (while still higher than human disease) is more comparable to human disease than syngeneic models.
This offers a secondary utility for murine tumor homografts after fulfilling unmet model needs, in offering a more human disease relevant platform for potential use instead of (or following) syngeneic models in a flexible and comprehensive drug discovery program.