Patient Derived Xenografts
Cancer is a devastating disease for which no definitive cure is currently available. While hundreds of potential anti-cancer therapeutics reach the clinical stage each year, the majority of them fail because the pre-clinical models used for their selection were not adequate. For many years, evaluation of anti-cancer efficacy of drug candidates has been carried out using tumor cell lines grown as xenografts in mice. However a disconnect has often existed between tumor response to therapy using this type of model and the one observed in patients. A possible reason for this was that prior to their xenografting, cancer cell lines were cultivated in vitro for many passages which could lead to the acquisition of new genetic/epigenetic alterations and clonal diversity that often does not reflect the original tumor. This, in addition to the lack of native human tumor stroma in cell lines-derived xenografts suggests that their architecture, clonal heterogeneity and response to therapy may not necessarily reflect those of the original human tumor.
The establishment of patient tumor derived xenografts (PDX) in mice has emerged recently as logical alternative to immortalized cell lines and other methods that are less translational. This technique consists of processing tumors obtained immediately after surgery into small fragments and engrafting them either subcutaneously or orthotopically into immunocompromised mice. Studies have confirmed that by using the PDX model, engrafted tumors maintained their original structure, histology and genetic profiles for at least five passages in mice. As a result, a strong correlation between PDX response to therapy and clinical outcome was observed, making this approach an extremely effective one for researchers in cancer to take.
The primary goal of the PDX project is to establish cancer patient personalized mouse models to assist in treatment decisions making and to utilize for biomarker discovery
Patient derived tumor samples will be engrafted and grown in immunodeficient mice. The animals are then subjected to treatment with candidate therapeutics (selected based on criteria that may or may not include analysis of tumor molecular data). Drug response results are communicated to the clinical team to help guide in formulating therapy options.
Drug response results of the PDX models can also be used for the identification of new cancer targets (drivers, master regulators…etc.) and biomarkers of prognosis and therapy response (monitoring). For this, molecular profiles (genetic and proteomic) of patient tumor samples will be compared between drug responders and non-responders. Differentially expressed molecules will be validated for their prognostic/diagnostic values.
A second goal of the PDX project is to carryout exploratory research to perfect/optimize this model and also to identify alternative solutions.
The predictive power of PDX models for therapy response has been reported to be as high as 90%. Although they may offers the best option to predict cancer patient response to therapy, the PDX models have major limitations relating to poor engraftment, time to obtaining results and operational cost. Because the engraftment rate of low grade tumors is much lower than that of the aggressive ones, not all patients who chose to participate in PDX protocols will be guaranteed personalized treatment recommendations based on preclinical testing results of their tumors. Even if this was the case, the cost to establish personalized PDX models could be prohibitive and the timetable to achieve deliverables not necessarily in line with treatment decisions.
To overcome some of these limitations, research effort at OPTIC will be directed at identifying new strategies to improve tumor engraftment in mice using engineered extracellular matrix mimetics. Particular emphasis will be to validate the efficacy of ECM extracted from De-cellularized organs corresponding to those from which the original tumor was excised. De-cellularized organs derived ECM (DOD-ECM) is widely used in bioengineering for tissue regeneration, therefore with regard to cancer it may provides a niche with features that closely resemble the one from which the tumor was excised. Its use in PDX models is expected to enhance tumor engraftment rate, particularly that of low grade tumors.
Alternative approaches will also be explored to reduce the time and cost needed to obtain meaningful preclinical tumor response results. Therapy response in PDX models have been shown to correlate with that of the corresponding patients (90% similarities). However establishing a personalized PDX model takes on average 4 to 6 months and depending how the patient health evolves, it may not be possible for the oncologist to wait such a long time before reaching a treatment decision. Alternatively, the development of a faster model to predict mice response to therapy (even if the prediction rate is lower than 90%) will likely benefit those patients who cannot benefit at all from the current PDX model.
A third goal of the PDX resource is to develop a platform for collaborations between the PDX resource and academic researchers inside and outside the university as well as with private entities. A close collaboration between the PDX resource, the cancer genome center and clinical teams has been a vital pathway to achieving this goal. Data sharing and pooled expertise of different teams is essential to interpret the results, to reach effective treatment decisions, to explore novel and challenging concepts, and also to request funding that will allow continuation of these investigations.
All PDX work involving animals is conducted in dedicated housing and surgical suites in the ICRC Animal facility under the OPTIC IRB and IACUC protocols. ICRC's animal facility is a fully AAALAC-accredited animal care and housing facility. Work is supported by the Institute for Comparative Medicine which administers the facility. ICM provides full veterinary care, administrative and regulatory oversight, and assistance with animal husbandry. All PDX work is conducted in dedicated space in the Herbert Irving Comprehensive Cancer Center.
The core holds monthly PDX interest group meetings in which we will discuss PDX projects each meeting, and there will be an opportunity for group discussion of PDX-related issues. The OPTIC Core is available for individual consultations with interested investigators on an as needed basis.
For detailed information on PDX models represented in the core, please email us at OPTICHELP@cumc.columbia.edu.