Abstract IA22: Studying drug resistance through PDX models

Emergence of drug resistance is the main limitation for a durable response to therapy. The mechanisms of such resistance need to be uncovered in order to identify those patients that are more likely to respond and/or develop novel strategies to overcome tumor adaptation to therapy.

Patient-derived xenografts can be established from patients at any stage of their treatment. However, samples collected before the exposure to the pharmacological pressure (therapy-naïve) and tumors from patients that progressed to therapy after an initial response (acquired resistance) are preferable.

Of particular interest are the models derived from outliers; that are either patients unexpectedly refractory to a given therapy (e.g. BRCA-mut tumors not responding to PARP inhibitors or HER2-positive tumors not responding to anti-HER2 agents) or patients that exhibited an exceptional response (magnitude/durability) to specific targeted agents.

There are at least two advantages in using patient-derived material for this kind of studies. The availability of virtually limitless tissue allows deep genomic and proteomic analysis of tumor cells that supposedly resemble the clinical scenario. Moreover, the possibility to perpetuate these tumors is crucial to confirm the resistance phenotype and test novel and more efficacious therapeutic options.

In my presentation I will include several examples of how patient-derived models have helped demonstrating the genuineness of previously hypothesized mechanisms of resistance to targeted therapy and have been instrumental to test combinatorial strategies that resulted in remarkable antitumor activity. Furthermore, I will show that patient-derived models can also serve as tools to test novel “smart” drug delivery systems.

Citation Format: Maurizio Scaltriti. Studying drug resistance through PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA22.