Project title: Establishing & characterizing a pancreatic neuroendocrine tumor mouse model with humanized telomeres

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Project Description: 

One of the challenges in studying pancreatic neuroendocrine tumors (PNETs) is that there hasn’t been a good animal model to test new treatments. Dr. Schramek and his team have developed a special mouse that can develop PNETs just like humans do. This mouse has the same genetic changes that are seen in human PNETs, and they can control when these changes happen. This will allow them to study how the cancer develops and which genes trigger progression. They will also use this mouse model to identify new drug targets.

What critical NET problem will you try to solve through your research?

Through genetic engineering, Dr. Schramek and colleagues will create and evaluate the first mouse model of pancreatic neuroendocrine cancer that recapitulates the genetic abnormalities observed in patients with aggressive tumors who also have poor prognosis. 

Why is this important?

The mouse model will enable the team to gain insights into the origin and progression of the disease to help develop new and more effective treatments.

How might your research improve the diagnosis and/or treatment of NETs? 

Currently, no mouse model of pancreatic neuroendocrine cancer exists, and Dr. Schramek hopes that their flexible design will allow them to engineer and study several genes implicated in the development of this cancer type. Ultimately, they hope to use these mouse models to design and test novel therapeutic strategies. 

What is your next step?

Once they have established faithful pancreatic neuroendocrine models, they will use those models to perform high throughput genetic and chemical screens as a first step towards the development of novel medicines that can help combat this disease.

 

Outcomes:

Pancreatic neuroendocrine tumor (PNET) patients have an overall mortality rate of 60%. Most of them have an unpredictable, highly variable clinical course. Insufficient understanding of PNET prevents the development of effective therapies and doctors from stratifying patients into 1) those with rapidly developing tumors who will benefit from early aggressive therapies and 2) those with indolent tumors who could be spared from unnecessary treatments and their toxic side effects. Recent genomic profiling studies of human PNETs revealed the prevalence and a strong association between MEN1/ATRX/DAXX mutations, alternative lengthening of telomere (ALT), and chromosomal instability (CIN), as well as the prevalence of alterations in the mTOR pathway and HLA locus. However, whether and mechanistically how these alterations affect PNET progression remain largely unknown. My project aims to develop the first metastatic PNET mouse model that recapitulates genomic, transcriptomic, molecular, histological, and clinical features seen in human PNETs through the concurrent knockout of multiple frequently mutated tumor suppressor genes in human PNETs in combination with modeling telomere dysfunction using genetically engineered mouse models and in vivo CIRSPR/Cas9-mediated gene editing. The successful establishment of a metastatic PNET mouse model will shed light into PNET etiology and empower the development of novel therapeutic strategies.

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