Project title: Molecular mechanisms in the progression of pancreatic neuroendocrine tumors

Project Description:  

More and more people are diagnosed with neuroendocrine tumors of the pancreas (panNETs) each year, and while some are curable, others are aggressive, incurable, and deadly. Though significant progress has been made in understanding a snapshot of the DNA mutations in panNETs at a single time point, there is still very little understanding of how these mutations change over time within individual patients and which mutations lead to aggressive disease over time. This project aims to understand which tumors are at risk for progression from low-grade to high-grade and why. We will use state-of-the-art DNA technologies to examine the genomes and epigenomes of panNETs at multiple time points within individual patients who have undergone serial biopsies over time, including in those with stable disease, those with progressive disease, and those who were high-grade at initial diagnosis.

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

This project will help us understand the precise sequence of DNA events that occur during progression over time from a low-grade to a high-grade aggressive panNET.

Why is this important?  

PanNETs are a heterogenous group of tumors with an increasing incidence. While some panNETs are slow growing and indolent, others can progress to aggressive, metastatic, incurable disease.  By mapping out the DNA changes that occur during tumor progression within individual patients, we hope to uncover drivers of progression and/or treatment resistance that can potentially serve as novel prognostic biomarkers or therapeutic targets for aggressive disease.

What will you do as part of this research project?

In addition to determining the molecular changes that occur during tumor progression, we will also explore the relationships between specific molecular alterations and clinical and histopathologic parameters.  

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

By comparing the genomic and epigenomic changes over time in panNETs that progress from low-grade to high-grade (G3) with those that do not progress to G3 and those that present as de novo G3 without prior treatment, we will gain a much deeper understanding of the sequence of molecular events involved in progression in cases with and without prior therapies and uncover drivers of progression and/or treatment resistance that can potentially serve as novel therapeutic targets for aggressive disease. Furthermore, this work will also reveal the molecular features of non-progressors and advance our understanding of the molecular and histopathologic classification of panNETs to better risk-stratify patients and inform clinical management

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