• A Mouse Model for Studying Pancreatic Tumor Resection and Adjuvant Therapy

A Mouse Model for Studying Pancreatic Tumor Resection and Adjuvant Therapy

Researchers have developed mice that develop focal, resectable pancreatic tumors closely resembling human pancreatic ductal adenocarcinomas (PDACs) that can be used to test adjuvant therapies, according to new research in the August issue of Gastroenterology. The authors show that administration of gemcitabine after resection of the tumors activates natural killer (NK) cell-mediated anti-tumor responses and inhibits local tumor recurrence.

Mice with single nodule tumors (A) after R0 surgical resection received adjuvant gemcitabine (C) or vehicle (B). The tumors exposed to gemcitabine contained fewer myeloid-derived suppressor cells (MDSCs) and more NK cells. These findings could account for the observation in clinical trials gemcitabine reduces local tumor recurrence.

Mice with single nodule tumors (A) after resection received adjuvant gemcitabine (C) or vehicle (B). In mice given gemcitabine. the tumors contained fewer myeloid-derived suppressor cells (MDSCs) and more NK cells. These findings could account for the observation from clinical trials that gemcitabine reduces local tumor recurrence.

Aggressive local tissue infiltration, including neural invasion and early metastasis, are typical clinical features of PDAC. Surgical resection is the only treatment option for non-disseminated PDAC. However, even after early complete resection, cancer recurs in 80%–85% of patients. Adjuvant chemotherapy has been proposed to increase times of disease-free and overall survival.

However, the number and types of adjuvant trials has lagged behind those of advanced-stage PDAC, in part due to the limited number of patients who undergo surgery. It has also been a challenge to study the effects of adjuvant therapies due to variation in surgical procedures, pathology evaluation (margin status), and times of follow up.

Preclinical models are therefore needed to test adjuvant therapies after tumor resection. Transgenic mice that develop pancreatic tumors are not good for these studies because they develop multifocal tumors and carry mutations in every pancreatic cell.

Gürlevik et al therefore devised an approach to create mice that develop local pancreatic tumors via mutations associated with human tumorigenesis. They developed an electroporation technique for site-specific transfection of the pancreatic parenchyma. Using this approach, they created 2 models of mice with focal deletion of P53 and expression of activated Kras (Kras G12V).

These mice form single tumors at the site of transfection within the pancreatic tail. The tumors have many histologic features of PDAC, including acinar-to-ductal metaplasia and pancreatitis.

However, Kras activation and p53 deletion did not fully reflect the aggressive infiltrative growth and metastatic spread of human PDAC. Gürlevik et al determined that active AKT2, a serine/threonine kinase that is activated in PDAC cells and believed to contribute to tumor progression, was required for local infiltration, neural invasion, and metastasis.

When these mice received adjuvant gemcitabine after R0 surgical resection, they had longer overall survival times, attributed to a reduction in local tumor recurrence, but not metastasis. This finding is similar to that observed for patients who received adjuvant gemcitabine in the large phase 3 trial that established the efficacy of gemcitabine as an adjuvant.

Gürlevik et al showed that adjuvant gemcitabine significantly increased recruitment of NK cells, as opposed to CD8+ cells, to the tumor margin.

In an editorial that accompanies the article, David W. Dawson and Martin E. Fernandez-Zapico explain that NK cells bridge innate and adaptive immunity, producing cytokines with anti-tumor activities. Although the increase in NK cells observed in the mouse model were associated with reductions in myeloid-derived suppressor cells and their immunosuppressive activity (see figure), it is possible that gemcitabine acted directly on residual tumor cells to modulate their susceptibility to NK cells.

Dawson and Fernandez-Zapico state that in addition to providing the proof-of-principle for this model itself, the study raises important questions about the therapeutic mechanisms of gemcitabine, given its effects were limited to the control of residual and recurrent local disease without effects on metastatic disease.

Gürlevik et al conclude that findings from this model are consistent with those from clinical trials, making it a good model for screening adjuvant strategies and studying their molecular mechanisms. It might also be used to develop biomarkers and customize adjuvant therapy.

However, all laboratories may not be able to use this model because it requires surgical expertise. Further studies are needed to determine whether this model can be used to test other anti-tumor agents.

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