Creation of a Prospective Monocentric Clinical-biological Database and Establishment of Preclinical Models in Pancreatic Adenocarcinoma (PA)

15019 Background: Efforts to find new therapies for human pancreatic ductal adenocarcinoma (PDAC) have not resulted in clear improvements on patient survival. Better knowledge of resistance mechanisms and redefiniton of molecular targets is essential to design more efficient therapies. The multifactorial origin of PDAC points to combined strategies as the therapy of choice, though the effective development of such strategies is hampered by the lack of optimal preclinical models. We have generated and validated optimized human PDAC models by direct implantation of fresh tumoral tissue into the pancreas of athymic mice. Methods: Thirteen pancreatic adenocarcinoma specimens from PDAC patients were obtained by surgical resection. From each specimen, several 10 mg-fragments were used to generate the corresponding intrapancreatic xenografted tumours. Eleven human PDAC orthotopic models have been successfully generated and perpetuated by succesive passages (up to 4). Histological and molecular analyses of both primary and xenografted tumors have been performed by tissue- array, western-blot and DNA sequentiation. Results: Initial engraftment rate ranged from 20 to 100% (mean 59%) and it improved with succesive passages (mean 76% at second and 90% at third generation). Ki67 expression and degree of differentiation in primary tumors correlated with xenograft growth kinetics. Furthermore, their spontaneous metastatic behaviour fairly reproduced the original patient dissemination patterns. Xenografted tumors kept the original architecture and expression patterns of common PDAC markers. Efficacy of several agents was tested on different xenografted tumors, validating this model and underlining its utility to define future therapeutic strategies for drug development and clinical trials. Conclusions: The orthotopic models described here are, probably, the closest resemblance to a patient clinical setting since they preserve human pancreatic structures, genotypic features and biological behaviour. From their use, biological relevant data could be drawn for future clinical trials and for testing new agents and new drug combinations since they represent, very likely, the most reliable animal models at present. No significant financial relationships to disclose.

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Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.289 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 289-289 ◽

Cited By ~ 3

Author(s):

Emily Pace ◽

Sharlene Adams ◽

Adam Camblin ◽

Michael Curley ◽

Victoria Rimkunas ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Adenocarcinoma ◽

Cell Lines ◽

Stage Iv ◽

Akt Signaling ◽

Preclinical Models ◽

Patient Response ◽

Receptor Complexes

289 Background: Gemcitabine, the first-line treatment for pancreatic cancer, has been improved by addition of nab-paclitaxel. However, patient response to this regimen is limited. Oncogenic insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling are associated with increased cancer risk and decreased response to anti-metabolites and taxanes. Therefore, we explored MM-141, a novel bispecific antibody that blocks ErbB3 and IGF-1 receptor (IGF-1R) signaling, in combination with nab-paclitaxel and gemcitabine in preclinical models of pancreatic cancer. Methods: Combinations with MM-141, gemcitabine, and nab-paclitaxel were investigated in pancreatic cancer cell lines, in vitro and in vivo. The effects of MM-141, gemcitabine, and nab-paclitaxel on tumor growth and signaling were measured by 3D spheroid growth, ELISA, Western, and mouse xenograft experiments. Results: In vitro studies show that IGF-1 and HRG are potent activators of AKT signaling, leading to increased pancreatic tumor cell proliferation and decreased sensitivity to gemcitabine and nab-paclitaxel. MM-141 inhibits ligand-induced AKT activation, induces IGF-1R and ErbB3 degradation better than a mixture of IGF-1R and ErbB3 antibodies, and sensitizes cells to gemcitabine and nab-paclitaxel, in vitro. In vivo, MM-141 combines favorably with a nab-paclitaxel/gemcitabine regimen, leading to curative outcomes in a subset of treated mice. Conclusions: ErbB3 and IGF-1R co-inhibition is required to inhibit AKT signaling in pancreatic adenocarcinoma cell lines. These receptors are associated with chemoresistance to gemcitabine and nab-paclitaxel, which is abrogated by co-administration with MM-141. MM-141-induced degradation of oncogenic receptor complexes is likely essential to reverse chemoresistance and enhance effects of the nab-paclitaxel/gemcitabine regimen. These data, taken together with wide-spread expression of IGF-1R and ErbB3 in Stage IV pancreatic adenocarcinoma tissue, support clinical exploration of a MM-141/nab-paclitaxel/gemcitabine regimen in frontline metastatic pancreatic cancer. Preparations for a randomized Phase 2 study are underway.

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