An In vivo Platform for Translational Drug Development in Pancreatic Cancer

Abstract

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials.The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

“…Biologically, the xenograft tumors closely recapitulate the biological features of pancreatic cancer and resemble the features of the originator tumor. In our hands, these tumors are notoriously more resistant to multiple anticancer agents perhaps reflecting better the clinical characteristics of pancreas cancer (22). IPI-504 significantly inhibited the growth of the tumors tested and, although less effective than the cytotoxic gemcitabine, was more active than other targeted agents.…”

“…Experimental Treatment Primary cancer specimens obtained from patients with resected pancreatic cancer at Johns Hopkins Hospital as reported previously were used (22). In brief, tumor specimens obtained from patients at the time of resection were implanted in 18 to 22 mice, which were randomized when reaching a tumor size of about 200 mm 3 into two groups with 5 mice each in either untreated control or IPI-504 treatment (75 mg/kg, thrice per week for 6 weeks).…”

“…Our group has focused in the development of patientderived human xenograft tumors as a preclinical model to study the activity of novel anticancer agents and to discover biomarkers of drug action in pancreatic cancer (22). In this study, we assessed the preclinical antitumor activity of the Hsp90 inhibitor, IPI-504, and sought to identify global molecular signatures of the agent using integrated iTRAQ proteomic analysis and gene expression profiling in human pancreatic cancer.…”

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

“…Because the PDX model has emerged as a better predictive model for evaluation of novel therapeutics (23, 27), we assessed the ability of MLN8237 to inhibit tumor growth in this model. The passaged tumors maintained the original tumor architecture observed in the initial patient tumor (Fig.…”

“…The PDAC PDX model was established as previously described (27). Briefly, de-identified tumors released by the Tissue Procurement Core Facility under an IRB-approved protocol were mixed with Matrigel and grafted into athymic (nu/nu) or NOD SCID gamma (NSG) mice.…”