Blog Post March 02, 2017

Patient-Derived Xenograft (PDX) Mice: Hacking the Haystack to Find Better Anti-Cancer Needles

Developing therapies for treating cancer can sometimes feel like searching for a single needle in a profoundly heterogeneous and highly mutable haystack. Accordingly, the models and tools used to study cancer must faithfully represent these characteristics and the underlying genetic and biologic processes that cause the disease. Without tumor models that accurately resemble human cancers, data generated in pre-clinical research often misses the mark in identifying truly translatable drugs and therapies that demonstrate clinical efficacy. Consequently, if you’re not using appropriate models, the needle that you think you have found in the cancer haystack may be just another stem of hay.

Cancer cell lines: As good as cancer models get?

Recently, the U. S. National Cancer Institute (NCI) retired their “NCI-60” panel of human tumor cell lines that for more than 25 years have been widely used as an anti-cancer drug screening platform1.  Although these and many other human tumor cell lines have been valuable resources, they are maintained in states that do not represent tumors in their native, biological environments:  specifically, such cell lines are maintained in vitro in tissue culture media, are handled in cell suspensions, are often immortalized through artificial genetic or chemical means, and represent uniform cell populations produced from repeated exposure to the same selection pressures. Cell lines can be extremely helpful for interrogating gene expression, cell signaling, and some cell biology, but in a xenograft setting, they often poorly reflect the patient tumors from which they were originally harvested. Primary tumors, in contrast, are three dimensional aggregations of multiple cell types that dynamically respond to stimuli and selection pressures; they offer a more promising strategy for finding possible therapies.

PDX mice: A better haystack 

PDX mice are increasingly powerful models in the cancer researcher’s tool kit. Unlike established and homogeneous tumor cell lines that have been passaged for many generations either in vitro or in vivo, PDX tumors are primary or low-passaged, heterogeneous tumor fragments that are implanted subcutaneously or orthotopically in an immunodeficient mouse host. The different cell types present in each PDX tumor fragment and their three-dimensional organization more closely mimics a tumor in a human patient, and may constrain how they grow and respond to therapies in clinically more relevant ways. 

Because PDX-engrafted tumor fragments are mixed cell populations, experiments utilizing them must then include enough engrafted individuals in each treatment group so that the variable drug responses due to fragment-to-fragment heterogeneity are captured.

PDX mice from JAX

Historically, PDX models have been difficult to establish in mice. Since strains such as our NSG™ (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ - 005557), which have severely “hacked” immune systems that lack their entire adaptive and a significant chunk of their innate immune responses, have become available, the rate with which these models are being created has accelerated. Since 2010, The Jackson Laboratory has been establishing new PDX models from all kinds of tumors and offering PDX-engrafted NSG™ mice to cancer researchers worldwide. Today, more than 400 models are available from our PDX Resource. For both off-the-shelf tumors that are part of our actively growing PDX Live™ program and for those maintained in our frozen, cryobanked stocks, researchers can obtain either:

1.) Donor Mice (academic researchers only): Single NSG™ mice bearing a subcutaneously-engrafted tumor. The tumors in these mice are intended for subsequent passaging and setting up study cohorts at your institution. These mice ship out when tumors are visibly confirmed.

2.) Study Cohorts (academic and for-profit researchers): Groups of tumor-bearing NSGTM mice for immediate study enrollment and not meant for further passaging. These mice ship out approximately two weeks post-engraftment. Because tumor growth rates can vary and we cannot predict which engrafted tumor fragments will grow well and which will not, we also will provide you with additional, “overage” mice at no charge to ensure that you receive the number of mice with viable and growing tumors that you require for your studies.

Recently, we updated and lowered pricing for our PDX mice to make them more affordable for academic researchers. Please contact our Technical Information Services for the most up-to-date prices.

Hay is for horses. What do you need?

Many therapeutic strategies are targeted to repress a particular gene’s expression or to inhibit its protein product.  Before investing in any PDX-engrafted mice and to help you to choose PDX models that are good candidates to include in your studies, we can provide slides with paraformaldehyde-fixed, paraffin-embedded tumor sections or snap-frozen (non-viable) tumor fragments so that you can validate your target gene’s expression level or check it for a specific genetic variant or biomarker. Our tumor bank is continually growing and for each model, we are rapidly working to add new characterization data, including RNA expression, gene variant, and copy number variant (CNV) analysis, tumor growth rates, histology, and responses to standard-of-care treatments. To find all of the PDX models that we offer and to view the data that currently is available for them, please visit the PDX portal within the Mouse Tumor Biology Database.

The search for cancer treatments is a daunting task, but improved models such as PDX mice that better resemble actual patient tumors should improve our chances for successfully finding elusive anti-cancer “needles” in the pre-clinical “haystack”. We hope and expect that wider PDX model development and usage will increase the number of compounds that successfully pass through clinical trials with demonstrable patient efficacy. 

Reference:

  1. Lefford H. 2016. US cancer institute to overhaul tumour cell lines. Nature. 530: 391. PMID: 26911756.