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

Hall JC, Marlow LA, Mathias AC, Dawson LK, Durham WF, Meshaw KA, Mullin RJ, Synnott AJ, Small DL, Krishna M, von Hoff D, Schüler J, Hart SN, Couch FJ, Colon-Otero G, Copland JA - J Transl Med (2016)

Bottom Line: The model presented here expresses the same IHC markers found in human PACC.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, 4500 San Pablo Road S., Jacksonville, FL, 32224, USA. Hall.Jason@mayo.edu.

ABSTRACT

Background: Pancreatic 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.

Methods: Fragments of biopsy tissue (5 mm(3)) 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 mm(3). Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation.

Results: The 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus

Evaluation of serum lipase enzyme levels. a Correlation plot of individual serum lipase levels compared to tumor volume indicated positive correlation with R2 = 0.6949 at day 15 when all groups were actively receiving chemotherapeutics. b Serum analysis for lipase secretion was performed on blood collected at pre-dose, and day 15. Data was plotted as mean ± standard deviation, n = 5. Asterisk indicated P < 0.05 for treatment group compared to placebo, n = 5. Erlotinib was not evaluable (ne) due to n = 3
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Fig3: Evaluation of serum lipase enzyme levels. a Correlation plot of individual serum lipase levels compared to tumor volume indicated positive correlation with R2 = 0.6949 at day 15 when all groups were actively receiving chemotherapeutics. b Serum analysis for lipase secretion was performed on blood collected at pre-dose, and day 15. Data was plotted as mean ± standard deviation, n = 5. Asterisk indicated P < 0.05 for treatment group compared to placebo, n = 5. Erlotinib was not evaluable (ne) due to n = 3

Mentions: Serum lipase levels were monitored on the blood of the xenografts to examine pancreatic lipase secretion compared to tumor volume [20]. On day 15, a positive correlation among the groups between serum lipase levels and tumor volumes in the xenografts was observed with R2 = 0.6949 (Fig. 3a). Among the groups, lipase secreted into serum (day 15) was only able to significantly decrease following oxaliplatin treatment (P = 0.046), reaching levels below pre-treatment. Bevacizumab treatment also led to lower serum lipase levels as compared to placebo, but it was not significant (P = 0.079). Of the eight monotherapies, only 5-FU and imatinib were unable to decrease serum lipase levels as compared to the placebo control (Fig. 3b).Fig. 3


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

Hall JC, Marlow LA, Mathias AC, Dawson LK, Durham WF, Meshaw KA, Mullin RJ, Synnott AJ, Small DL, Krishna M, von Hoff D, Schüler J, Hart SN, Couch FJ, Colon-Otero G, Copland JA - J Transl Med (2016)

Evaluation of serum lipase enzyme levels. a Correlation plot of individual serum lipase levels compared to tumor volume indicated positive correlation with R2 = 0.6949 at day 15 when all groups were actively receiving chemotherapeutics. b Serum analysis for lipase secretion was performed on blood collected at pre-dose, and day 15. Data was plotted as mean ± standard deviation, n = 5. Asterisk indicated P < 0.05 for treatment group compared to placebo, n = 5. Erlotinib was not evaluable (ne) due to n = 3
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4862141&req=5

Fig3: Evaluation of serum lipase enzyme levels. a Correlation plot of individual serum lipase levels compared to tumor volume indicated positive correlation with R2 = 0.6949 at day 15 when all groups were actively receiving chemotherapeutics. b Serum analysis for lipase secretion was performed on blood collected at pre-dose, and day 15. Data was plotted as mean ± standard deviation, n = 5. Asterisk indicated P < 0.05 for treatment group compared to placebo, n = 5. Erlotinib was not evaluable (ne) due to n = 3
Mentions: Serum lipase levels were monitored on the blood of the xenografts to examine pancreatic lipase secretion compared to tumor volume [20]. On day 15, a positive correlation among the groups between serum lipase levels and tumor volumes in the xenografts was observed with R2 = 0.6949 (Fig. 3a). Among the groups, lipase secreted into serum (day 15) was only able to significantly decrease following oxaliplatin treatment (P = 0.046), reaching levels below pre-treatment. Bevacizumab treatment also led to lower serum lipase levels as compared to placebo, but it was not significant (P = 0.079). Of the eight monotherapies, only 5-FU and imatinib were unable to decrease serum lipase levels as compared to the placebo control (Fig. 3b).Fig. 3

Bottom Line: The model presented here expresses the same IHC markers found in human PACC.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, 4500 San Pablo Road S., Jacksonville, FL, 32224, USA. Hall.Jason@mayo.edu.

ABSTRACT

Background: Pancreatic 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.

Methods: Fragments of biopsy tissue (5 mm(3)) 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 mm(3). Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation.

Results: The 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus