AACR 2014: Multifactorial Biological Processes Govern Engraftment of Patient-Derived Tumor Tissue in Immunodeficient Mice
Multifactorial biological processes govern engraftment of patient-derived tumor tissue in immunodeficient mice
David M. Vasquez-Dunddel1, Gilson Baia1, Amanda Katz1, Daniel Ciznadija1, David Sidransky2, Keren Paz1.1Champions Oncology, Baltimore, MD; 2Johns Hopkins University, Baltimore, MD
TumorGrafts (also known as patient-derived xenografts) are a valuable tool for the personalization of oncology treatment, as well as development of new cancer therapeutics. Tumor explants are engrafted into immunodeficient mice and allowed to develop prior to screening against a panel of drugs or drug combinations to assess which best inhibit tumor growth. These models capture the chaotic heterogeneity, histopathology, and biology of the original tumor, as well its 3-dimensional interaction with the surrounding stroma and other cells migrating into the tumor environment. TumorGrafts will serve basic and clinical research groups as an increasingly valuable preclinical model of cancer. One important variable governing the generation of these models is the take rate, or the percentage of patient tumors that successfully engraft and grow in the mice. This is a potentially critical limitation to applying these preclinical models for improving patient treatment and advancing novel drug regimens to the clinic. Hence, there is a need to understand and exploit the mechanisms that influence take rate in order to ensure that the majority of tumor explants readily engraft and expand. We describe here our experience in optimizing the engraftment of patient tumor tissue in immunodeficient mice. We found a number of factors contribute to take rate including tumor type, tissue quantity and quality, engraftment site, oxygenation state, neovascularization and the presence of extracellular stromal components and cells. We have also uncovered a correlation between the growth rate of tumors in the mice and the clinical aggressiveness of the original malignancy, information that may be useful in guiding clinical management. Moreover, we describe how we are now able to consistently use biopsy material rather than surgical explants to establish TumorGrafts, a crucial step forward that allows this technology to benefit patients diagnosed with early-stage cancers or where surgery is not indicated. Although engraftment of patient tumor tissue in immunodeficient mice is a complex process, with multiple factors impacting success, we have effectively optimized this process, improving our take rate and at the same time, reducing the time to obtaining drug screening results, all without compromising tumor integrity.