M402, a heparan sulfate mimetic and novel candidate for the treatment of pancreatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4056-4056 ◽  
Author(s):  
Birgit Corinna Schultes ◽  
Martijn P.J.K. Lolkema ◽  
Chia Lin Chu ◽  
He Zhou ◽  
Alison Long ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Heparan Sulfate ◽  
Human Study ◽  
Tumor Stroma ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Heparin Binding ◽  
Shh Signaling ◽  
Mesenchymal Transition ◽  
Genetically Engineered Mouse Model

4056 Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.

scholarly journals Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0140253 ◽  
Author(s):  
Jamie D. Weyandt ◽  
Benjamin L. Lampson ◽  
Sherry Tang ◽  
Matthew Mastrodomenico ◽  
Diana M. Cardona ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Genetically Engineered ◽  
Wild Type ◽  
Genetically Engineered Mouse Model

scholarly journals Anti-Tumour Efficacy of Capecitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e67330 ◽  
Author(s):  
Aurélie Courtin ◽  
Frances M. Richards ◽  
Tashinga E. Bapiro ◽  
Jo L. Bramhall ◽  
Albrecht Neesse ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Model

scholarly journals Recapitulation of Genetic Predisposition to Medulloblastoma in Human Neuroepithelial Stem Cells

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Jignesh Tailor ◽  
Miller Huang ◽  
Austin Smith ◽  
William A Weiss
Keyword(s):  
Stem Cell ◽  
Genetic Predisposition ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Gorlin Syndrome ◽  
Orthotopic Transplantation ◽  
Cells Of Origin ◽  
Genetically Engineered Mouse Model ◽  
Stem Cell Lines ◽  
Induced Pluripotent

Abstract INTRODUCTION Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, long-term propagating hindbrain cells that are representative of the cerebellar primordium. METHODS First we transduced NES cells with N-MYC to test whether NES cells can be transformed to brain tumour initiating cells. In parallel, we generated induced pluripotent stem (iPS) cells from patient's with Gorlin syndrome (PTCH mutation) and subsequent differentiated these cells to NES cells to recapitulate the genetic predisposition to medulloblastoma formation. These NES cells were orthotopically transplanted into mouse cerebellum to test their tumor forming capacity. RESULTS Following orthotopic transplantation of NES cells transduced with N-MYC, we observed formation of medulloblastoma. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. CONCLUSION These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma

Preclinical immunotherapy studies using an orthotopic pancreatic cancer mouse model.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 324-324
Author(s):  
Despina Siolas ◽  
Orlando Aristizabal ◽  
Kate Byrne ◽  
Lawrence P. Leichman ◽  
Robert H. Vonderheide ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Small Animal ◽  
Pancreatic Tissue ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Therapeutic Interventions ◽  
Cancer Mutations ◽  
Tumor Microenviroment ◽  
Aggressive Clinical Course

324 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. The advent of new mouse models of pancreatic cancer have accelerated our understanding of tumorigenesis and enabled preclinical testing of experimental therapeutics with a desire to translate these findings into meaningful clinical treatments. Methods: We have developed a model where pancreatic cells obtained from a KrasG12D;Trp53R172H genetically engineered mouse can be cultivated in two dimensional cell culture and implanted into the pancreas of a immunocompetent syngeneic mouse allowing for tumor formation in situ. In addition, we are using this model to study the effectiveness of new drug combination therapy such as gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy using overall survival as a primary endpoint. Results: These cells generate tumors of five millimeter diameter within two weeks of implantation with 100% efficiency. Because cancer cells are seeded in the context of normal surrounding pancreatic tissue, this model is not hampered by the genetic field effect of expressing cancer mutations in the entire pancreatic organ, allowing for the study of the tumor microenviroment. Responses to therapeutic interventions can be non-invasively monitored through small animal high resolution ultrasound. Conclusions: Our orthotopic pancreatic cancer mouse system is an effective model for pre-clinical studies of tumorigenesis, immunotherapy and examination of the tumor microenvironment. Future experiments will focus on exploiting this system for identifying potent immunotherapy and chemotherapy combinations and for detecting biomarkers of efficiency.

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