Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma.
OBJECTIVE
Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design.


METHODS
We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slices derived from pancreatic ductal adenocarcinoma PDX tumors were arrayed in a 96-well plate and screened against clinically relevant regimens within 3 to 5 days. The correlation between the sensitivities of tissue slices to the regimens and patients' clinical responses and outcome were statistically analyzed. The results of LTSA assay were further confirmed with biochemical methods in vitro and animal PDX model in vivo RESULTS: The ex vivo tissue slices remain viable for at least 5 days, and the tumor parenchyma, including stroma, vascular structures, and signaling pathways, are all retained. The sensitivities of the ex vivo tissue slices to gemcitabine and irinotecan was consistent with the clinical responses and outcomes of the patients from whom the tumorgrafts were derived (r = 0.77; P = 0.0002). Retrospective analysis showed that the patients who received LTSA-sensitive regimens had remarkably longer progression-free survival than patients who received LTSA-resistant regimens (16.33 vs. 3.8 months; n = 18, P = 0.011).


CONCLUSIONS
The results from these PDX and LTSA methods reflect clinical patients' responses and could be used as a personalized strategy for improving systemic therapy effectiveness in patients with pancreatic cancer. Clin Cancer Res; 22(24); 6021-30. ©2016 AACR.
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
David
D
Roife
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Bingbing
B
Dai
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Ya'an
Y
Kang
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mayrim V Rios
MVR
Perez
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Michael
M
Pratt
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Xinqun
X
Li
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jason B
JB
Fleming
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D064593:Heterografts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000077146:Irinotecan; D002166:Camptothecin; D000093542:Gemcitabine