Optimizing Targeted Agents Development In Pancreatic Cancer: A Fine-Needle Aspirate Biopsy (Fnab) Based Ex Vivo And In Vivo Assay.

3002 Background: While targeted therapeutics effectively inhibit tumor growth with less toxicity than conventional chemotherapy, in general cancer patients show highly variable responses to them. This study aimed to develop and validate methods that permit the prediction and assessment of the efficacy of targeted therapeutics by using tumor fine needle aspiration biopsy (FNAB) samples Methods: A series of human primary pancreatic cancer were xenografted in nude mice by implanting tumor materials from surgically resected pancreatic cancer patients. Animals were treated with an epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and the mTOR inhibitor temsirolimus or vehicle. Tumors were sampled by FNAB prior to (baseline) and after therapy. Tumor cells obtained by FNAB at baseline were exposed to erlotinib or temsirolimus for six hours ex vivo to prospectively predict tumor response. The degree of inhibition in phosphorylation of ERK1/2 and S6-Ribosomal Protein (S6-RP) downstream to EGFR and mTOR, respectively, were assessed by Western blot to determine the efficacy of the targeted drugs ex vivo and in vivo. The results were correlated with drug-mediated changes in tumor volumes. The effect of drugs on protein phosphorylation ex vivo was also analyzed in patient FNAB samples to show the clinical feasibility of the approach. Results: The degree of inhibition of target pathway activity in tumor cells treated with erlotinib or temsirolimus ex vivo closely correlates with tumor sensitivity in vivo. Xenograft animals sensitive to therapy showed the highest average inhibition of target protein phosphorylation in ex vivo assays, whereas tumors resistant to drugs gave the lowest one. Patient tumor samples yielded adequately cellular material to analyze the effect of erlotinib and temsirolimus in ex vivo assays. Conclusions: FNAB can be used to test ex vivo tumor response to targeted agents. These effects predicted pharmacodynamic as well as antitumor effects in a serie of pancreatic cancer xenografts. Implementation of these novel methods in clinical trials may be useful to identify patients that are likely to benefit from targeted therapeutics before being exposed to drugs and their potential side effects. No significant financial relationships to disclose.