Developing Patient Derived Xenografts (PDX’s)

Despite dramatic advances in treating childhood cancer, there is a long way to go before the cure rates and the long-term consequences of current therapy are acceptable. However, developing more effective agents for those children not currently cured and less toxic therapy to others poses significant challenges. First, numerous hurdles limit the capacity for new drugs to be tested in clinical trials in children. Second, many early-phase clinical trials for testing the newest agents are focused on children with relapsed/recurrent disease. Such tumors are heavily pretreated and may poorly reflect how effective a new drug may be if used earlier in the course of their disease. Finally, some minority and underserved populations – such as Hispanic populations common across Texas – have outcomes that are worse than the general population, and these populations may be poorly represented in the few clinical trials that are available.

To overcome these challenges, we are developing and validating preclinical models that represent the genetic diversity of childhood cancer from the populations of children what we serve in Texas. We have shown that transplantation of cancer tissue from a child into immune-deficient mice (a process known as patient derived xenografts; PDXs) can generate experimental models that are valuable to identify novel treatments. Indeed, some of the drugs and drug combinations shown to be active in PDX models have been advanced to clinical trials in children. However, the current models do not fully represent the genetic diversity known to exist in the spectrum of childhood cancers. Further, very few models have been derived from Hispanic children known to have poorer outcomes.

We have established a coordinated effort between UT Health at San Antonio and UTSW to develop and characterize new PDX models from children, focusing on Hispanic and underserved groups in Texas. These models are being characterized using state-of-art molecular approaches, and they will be made available freely to pediatric cancer researchers in Texas and more broadly. We have already distributed childhood cancer models to over 200 laboratories, and believe that these have been important in further understanding the biology and therapy of childhood cancers. The models have also spurred industry partners to focus on pediatric cancer therapeutics at several large pharmaceutical companies (Eli Lilly, Novartis, Pharmacia, Genentech/Roche) as well as many smaller biotech companies. Generating additional PDX models, representing a renewable resource, will not only enhance our ‘coverage’ of genetic diversity of childhood cancer, it will provide urgently needed materials that will enhance research into childhood cancer worldwide.