New research from the University of California Davis and The Jackson Laboratory provides more evidence that patient-derived xenografts (PDXs), human tissues implanted in immunocompromised mice, can provide powerful insight into cancer mechanisms and therapies.
Researchers led by Ralph de Vere White of UC Davis and including James Keck, Susan Airhart, Carol Bult and Edison Liu of JAX established engraftments of 22 bladder cancer specimens in NSG mice, which are developed to accept human tissue transplants. In a paper published on August 13 in PLOS One, they show that the cancer tissues retained the characteristics of the parent tumors following implantation, including sharing 92%-97% of genetic aberrations. Therefore, therapy efficacy studies using PDXs are likely to accurately reflect what happens with the cancers in patients.
Next, the researchers used the PDX platform to perform efficacy studies of combination therapy and therapy resistance. For example, they tested an EGFR/HER2 dual inhibitor on two HER2 expressing PDX bladder cancers, finding one effective and one not. For the non-responding tumor, however, a different inhibitor (for PIK3CA) subsequently proved effective. The researchers also screened for secondary resistance pathways activated after administration of front-line therapy. In one PDX tumor, they discovered secondary resistance via the activation of the MAPK/ERK and PIK3CA-AKT pathways, and they were able to significantly increase progression-free survival with inhibition of those pathways.
Quickly determining effective first-line and second-line therapies based on a tumor’s mutations (molecularly guided targeted therapy, or MTT) represents a promising application of precision medicine. The paper provides further evidence that PDX models provide a powerful system for quickly finding the right front-line therapies and mechanisms of secondary resistance for individual patient tumors.