Preclinical Modeling of Novel Therapeutics in Patient Derived Xenografts of Solid Tumors

Abstract

<p>Due to the failure of many drugs in the transition from the preclinical setting into clinical trials, better mouse models of cancer are needed. To this end, our lab has created a patient derived xenograft (PDX) system by processing tumors as they are resected from the patient and directly injected them into mice without the intermediate step of cell culture. This allows us to work with tumors that are very similar to the original patient tumors, unlike cell lines, which have many alterations before they are used for xenograft work. Our PDX model is ideal for studying novel therapeutics in vivo, as they accurately mimic the human tumor setting. </p><p>One current difficulty clinicians in oncology have is directing patients to the therapy that will be most effective and least toxic to them. Next-generation sequencing platforms address this problem by providing clinicians an overview of their patient’s mutation status. It is not known, however, the most cost effective sequencing platform that gives sufficient data to properly direct a patient’s therapy. Therefore, I tested panels of two different sizes to determine how many genes need to be sequenced to sufficiently treat a group of patients. I then directed mice into therapy based upon the results from each of the panels. I determined that while a 400 gene panel does give enough mutation data to guide therapy, many of the mutations are not predictive and require further testing. </p><p>Exercise is a potential therapy that has recently been shown to be somewhat effective in mouse models of cancer, as well as decreasing time to progression for cancer patients. However, it is unclear how exercise therapy decreases the growth of tumors. To explore this in detail, I used our PDX model and investigated whether three different colon cancer PDXs would respond to exercise. I found that two out of the three did respond to exercise, as evidenced by decreased tumor growth. To investigate the mechanism of the effects of exercise therapy, I used gene set enrichment analysis and found that markers of hypoxia are decreased in tumors of mice that have exercised compared to those that were sedentary during the experiment. Using immunofluorescence, we confirmed that there is a decrease in hypoxia in tumors of mice that have exercised, giving one explanation for the decrease in tumor growth and aggressiveness in mice that exercise compared to those that are sedentary.</p>