Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Abstract

BackgroundPancreatic acinar cell carcinoma (PACC) is a rare malignancy, accounting for <1 % of all pancreatic neoplasms. Very few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic PACC who achieved prolonged survival following doxorubicin treatment. Personalized treatment was based on molecular and in vitro data collected from primary cells developed from their liver metastasis. We now report the characterization of a patient derived tumor xenograft (PDTX) mouse model that originated from this patient’s PACC liver metastasis.MethodsFragments of biopsy tissue (5 mm3) from PACC liver metastasis were implanted into athymic nude mice. Tumors were grown and passaged from the host mice into new mice to be tested for therapeutic response. Immuno-histochemical (IHC) biomarkers were used to confirm that the PDTX model represents human PACC. The antitumor activities of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) were tested. Tumor size was measured over 74 days or until they reached an endpoint volume of ~800 mm3. Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation.ResultsThe model presented here expresses the same IHC markers found in human PACC. In the chemotherapy study, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase levels and increased healthy acinar cells. Bevacizumab also produced a significant growth response, but the effect was not prolonged as demonstrated by oxaliplatin treatment. The other chemotherapies had moderate to little effect, particularly after treatment ceased. Mutations in DNA repair genes are common in PACC and increase tumor susceptibility to oxaliplatin. To explore this we performed IHC and found no nuclear expression of BRCA2 in our model, indicating a mutation affecting nuclear localization. Gene sequencing confirms BRCA2 has a homozygous gene deletion on Exon 10, which frequently causes a protein truncation.ConclusionsIn summary, we report the development and characterization of the first and only preclinical PACC PDTX model. Here we show sustained anti-tumor activity of single agent oxaliplatin, a compound that is more effective in tumors that harbor mutations in DNA repair genes. Our data shows that BRCA2 is mutated in our PACC model, which could contribute to the oxaliplatin sensitivity observed. Further studies on this rare PACC model can serve to elucidate other novel therapies, biomarkers, and molecular mechanisms of signaling and drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0875-z) contains supplementary material, which is available to authorized users.

Exome Sequencing of Pancreatic Acinar Carcinoma Identified Distinctive Mutation Patterns

“…BRCA1/2 -deficient tumors are sensitive to platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors, which may provide better clinical outcome. This has been supported by continuous response to oxaliplatin in a xenograft murine model derived from the ACC patient with somatic BRCA2 mutation 51 . In humans, complete remission or prolonged relapse-free survival has been observed in patients who have metastatic ACC with either somatic or germline BRCA2 mutation treated with cisplatinum or oxaliplatin 10,52,53 …”

Optimizing Chemotherapy of Pancreatic Acinar Cell Carcinoma: Our Experiences and Pooled Analysis of Literature

“…17 In the preclinical PACC patient–derived tumor xenograft model, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase level, and increased healthy acinar cells. 45 Yoo et al 46 reported that oxaliplatin-containing chemotherapy against PACC has improved activity compared with gemcitabine. It was indicated that chemotherapeutic agents used in treating colorectal cancer might be effective in ACC of the pancreas.…”

Derivation of pancreatic acinar cell carcinoma cell line HS‐1 as a patient‐derived tumor organoid

“…Second, Panc‐4 cells, which secrete lipase in the supernatant, were not characterized in detail in vitro 25 . Although its acinar properties seemed verified in histological analysis when grown as xenografts, 56 sufficient in vitro data were not provided. Third, Faraz‐ICR cells express mesenchymal markers such as vimentin and desmin, but not epithelial markers, which are unlikely to represent ACC 27 .…”