One of the most widely used methods of modeling human tumor biology for preclinical research is the use of xenografts. Xenografts are generated by implanting human tumor cells under the skin or directly into the organ type of interest in immunocompromised rodents that will not reject the human tumor cells. Depending on the number of tumor cells injected and the type of cancer, tumors will develop within 1-4 months 1. This process can be done with human cancer cell lines, homogenized tissue taken from a patient or from solid tumor samples taken from a patient. The use of patient-derived xenografts, either as established cell lines taken from a patient, tissue slurries, or solid tumor xenografts aim for a more accurate representation of human tumor physiology, heterogeneity, and drug response.

 

Xenograft development using established human cancer cell lines has also been incredibly important for examining the role of specific driver mutations on drug resistance and response. Xenografts also give us the opportunity to study important cell lines that are otherwise difficult to culture in vitro. VCaP cells are a prostate cancer cell line that have a wild type androgen receptor but can proliferate in an androgen-independent manner – this makes them an ideal model for the study of castration-resistant prostate tumors 2. They are, however, very difficult to grow in in vitro cell culture as the litany of researchers seeking help with this line on ResearchGate can likely attest to. Interestingly, when injected into OncoRats® for xenograft development, VCaP cells form tumors, in 90% or more of the rats, with volumes ranging from 12,000-16,000mm3 in just 36 days. See OncoRat VCaP case study and figures below.

 

 

Another difficult cell line that has proven to be a better model in xenograft-form is the non-small cell lung cancer (NSCLC) cell line, H358 (a.k.a NCI-H385, H-358). H358 is valuable to the NSCLC field because it is wild-type for all of the most common oncogenes and tumors suppressors in NSCLC with the exception of an oncogenic, KRAS-activation mutation. The majority of the targeted therapies that have been examined for use in NSCLC to this point have been targets of the EGFR – KRAS – BRAF – MEK – ERK signaling kinase cascade as oncogenic addiction to these growth factor signals are commonly observed in NSCLC. The earliest approved targeted therapies in NSCLC targeted EGFR, and activated KRAS is a counter-indication of anti-EFGR therapy use. Despite the KRAS activation mutation, H358 cells are exquisitely sensitive to anti-EGFR therapies making this cell line the unicorn-model for trying to understanding the complex relationship between KRAS mutations and anti-EGFR drug resistance. Xenograft development using H358 cells in rats demonstrated that these once culture-defiant cells formed tumors with volumes between 2000-3000mm3 within 25 days. See case study data.

 

Xenograft models using cell lines are an imperative preclinical model for understanding the role of specific oncogenic drivers, tumor suppressor losses, and drug action in homogenous cancer cells – without these models, understanding mechanism of action and the full contribution of mutations is nearly impossible. By utilizing the OncoRat to broaden xenograft screening opportunities to include targeted models such as VCaP and H358 that are not feasible in vitro or in the mouse can result in better efficacy data and fewer drug failures.

 

1. Richmond, A.; Su, Y., Mouse xenograft models vs GEM models for human cancer therapeutics. Disease Models & Mechanisms 2008, 1 (2-3), 78-82.

2. Eskra, J., Culture methods for VCaP prostate cancer cells. 2015.