TY - JOUR
T1 - Optimizing the development of targeted agents in pancreatic cancer
T2 - Tumor fine-needle aspiration biopsy as a platform for novel prospective ex vivo drug sensitivity assays
AU - Rubio-Viqueira, Belen
AU - Mezzadra, Heather
AU - Nielsen, Matthew E.
AU - Jimeno, Antonio
AU - Zhang, Xianfeng
AU - Iacobuzio-Donahue, Christine
AU - Maitra, Anirban
AU - Hidalgo, Manuel
AU - Altiok, Soner
PY - 2007/2
Y1 - 2007/2
N2 - At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross anti-tumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit.
AB - At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross anti-tumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit.
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U2 - 10.1158/1535-7163.MCT-06-0388
DO - 10.1158/1535-7163.MCT-06-0388
M3 - Article
C2 - 17308050
AN - SCOPUS:33847396528
VL - 6
SP - 515
EP - 523
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 2
ER -