Zevatars; the future of personalized cancer medicine
Personalized medicine offers a more informed strategy to treat cancer patients. Although promising, the efficacy of targeting therapy based on a patient’s molecular profile is still difficult to predict. Currently, ex vivo models such as patient derived mouse xenograft (mPDX), organoid culture, and conditionally reprogrammed cells (CRC) are being developed to improve the prediction of chemotherapy response. These models require significant expansion of tumor cells for drug testing requiring relatively long wait times, which introduces potential for changes in genetic and epigenetic characteristics of the tumor. Moreover, these models do not consider the tumor microenvironment, including the immune system which is important for cancer therapy. Therefore, to compliment these models, we have developed patient-derived xenografts in zebrafish embryos or ‘Zevatars’ that directly samples the patient’s tumor, is rapid enough to benefit patients with aggressive disease, allows for high-throughput drug screening, and provides a readout that is not simply a surrogate for cell growth. The assay is performed by implanting labelled pieces of patient tumor tissue (fresh or cryopreserved) into 2 dpf embryos, treating with drugs, monitoring tumor behaviors, including size changes, cell migration, and metastasis through imaging. The best treatment for a given patient can be determined in less than one week. In addition, we can generate Zevatars from multiple tumor types including pancreatic cancer and liver metastasis. Our results show that tumor biopsy tissue differentially responds to standard of care drugs. Importantly, the response varies greatly from patient to patient, thus recapitulating patient tumor behavior in the clinic. However, one major limitation of the Zevatar is that we cannot study adaptive immune responses or cancer immunotherapy in this model, though we have observed macrophage homing to cancer xenografts suggesting a role for the innate immune system. Hence we are developing a humanized fish in which we replace the zebrafish hematopoietic system with a human hematopoietic system via stem and progenitor cell transplantation (HSPC). If successful, we can then predict chemotherapy and immunotherapy effectiveness by using a Zevatar with a patient’s own HSPCs coupled with their tumor biopsy. In developing this technology we can provide a rapid and relatively cost-effective method for personalized cancer diagnostics.