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.

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​      A second goal of the PDX project is to carryout exploratory research to perfect/optimize this model and also to identify alternative solutions.

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     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.

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​​     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.

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     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.