Prolonged Ex Vivo Animation of Tumor-bearing Liver as the Ideal Tumor Model System
The ability to recapitulate the complexities of solid human tumors for the purposes of drug development and testing has been, and remains, a major obstacle in the progress of cancer care. Despite great efforts expended on pre-clinical optimization using existing models, most drugs simply fail to demonstrate efficacy when subjected to phase III clinical trial scrutiny. This is evidenced by the fact that 95% of oncology drugs fail to progress from phase I trials to FDA approval. Our interpretation is that the currently available model systems lack the appropriate clinical predictive power. The reasons for the inadequacies of these model systems, which are largely based upon cell lines, mouse models, or patient-derived xenografts, are myriad, but are almost certainly related to the absence of the human stromal component and its intricate relationship with tumor cells. Additionally, the human immune system and its complex interaction with the tumor is not recreated in any existing preclinical models. Modeling the multi-faceted interactions between human cancer cells and the multitude of various stromal components, including activated fibroblasts, immune cell infiltrate, and the abnormal vasculature is, at present, an impossibility. However, the potential exists for a new model of human malignancy. Since 2005, ex vivo perfusion has been used to bridge organs from donation to transplantation. The bounds of these perfusion systems have, however, not been tested or optimized for longer than 6 hours at normothermic temperature. Our lab is exploring the use of these organ perfusion systems to create a new tumor model of the human liver as a site of metastatic disease.
Using existing tissue collection and cancer treatment protocols at the NIH Clinical Center, trials of this system on liver specimens have already commenced. As members of the Surgical Oncology Program, our lab has unparalleled access to human tissue specimens directly as they are removed from a patient’s body and transferred to the perfusion machine, which allows us to mimic the natural blood flow to the liver through both a portal and an arterial system. The tissue specimen is maintained at normothermia (37⁰C) while our team performs hourly point of care labs on the tumor-bearing organ and adjusts the perfusate composition accordingly. As this new model is optimized, we foresee the need to modify the machine in order to prolong viability.
One application of particular interest to the lab is the identification of potential metastatic sites: cells from the patient’s tumor are dissociated, labelled, and injected into portal inflow cannula. A fluorescence detector is used to track the migrating cells and identify where they settle, in order to guide biopsies for high-resolution microscopy and histopathological analysis of these sites.
A summer student will work on further optimization of this model, with the specific focus determined by the project needs and student interest. Possibilities include mechanical modifications to the Liver Assist machine, biochemical manipulations of the perfusion fluid, optimization of the fluorescence detector. The BESIP student working in this area should have background and interest in mechanical engineering, human physiology, and biochemistry. Through working closely with the interdisciplinary team, the BESIP intern will gain valuable hands-on experience with multiple procedures and technologies and can expect to gain experience in various areas of cancer and biomedical research.
To discuss more specifics of this summer project, please feel free to contact Dr. Jonathan Hernandez.