Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma

Abstract

Purpose Translation of the 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. Experimental Design 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 3-5 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 pancreatic cancer patients.

Clinical candidate and genistein analogue AXP107‐11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein‐coupled estrogen receptor signaling

“…In our study, we noted potent chemoenhancing effects at low concentrations (1 μmol/L), which were also corroborated in vivo (AXP107‐11 substance). Although higher doses were used for ex vivo (organotypic cultures) and in vivo (PDX models) due to methodological considerations, ie measuring effects in a shorter time frame than in the clinical setting, this still enables prediction to anticancer drugs in PDAC patients . While additional mechanisms cannot be excluded, and it is possible that our RNA‐Seq analysis of treated cell lines and ex vivo analyses which used higher concentrations also picked up unspecific effects, our data do identify GPER1 as a main mechanism.…”

Precision Oncology: The Road Ahead

“…As the median time frame for molecular profiling and data processing in precision oncology trials is 2–4 weeks, the method is not suitable for testing genomics-guided therapies derived from the same biopsy, unless combined with other models. Recently, organotypic slice cultures established from pancreatic ductal adenocarcinoma PDX models were used to screen against clinically relevant drug regimens in a 96-well format, demonstrating consistency between sensitivity of organotypic cultures and the clinical responses of donor patients [215]. …”

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

“…However, in vitro and in vivo studies using human pancreatic ductal adenocarcinoma (PDAC) cell lines and patient‐derived xenografts (PDX) have assessed auranofin's anticancer activity . Sensitivity to the compound was determined based on IC 50 values, which were in the 5 to 10 μM range for 13 PDX cell samples and 15 mg auranofin/kg given intraperitoneally significantly decreased or inhibited tumor progression and metastasis in PDX models . High TrxR1 and low NRF2 expression correlated with greater PDAC resistance to auranofin.…”

“…177 Sensitivity to the compound was determined based on IC 50 values, which were in the 5 to 10 μM range for 13 PDX cell samples and 15 mg auranofin/kg given intraperitoneally significantly decreased or inhibited tumor progression and metastasis in PDX models. 177,178 High TrxR1 and low NRF2 expression correlated with greater PDAC resistance to auranofin. Although there are currently seven cancer trials listed under the https://clinicaltrials.gov site, no results have as yet been reported on their clinical outcomes.…”