Etay Ziv, MD, PhD, Studying NET Progression in NETRF-Funded AACR Research Project

Understanding the progression of NETs from low grade to high grade

At its recent virtual awards event, the American Association for Cancer Research (AACR) recognized the innovative NETRF-funded research on pancreatic neuroendocrine tumors being conducted by Etay Ziv, MD, PhD.  Dr. Ziv, an interventional radiologist at Memorial Sloan Kettering Cancer Center in New York, leads a translational research study that aims to understand the process of how pancreatic NETs progress from low grade to higher, more aggressive grade tumors.

One of the best prognostic indicators of patient outcomes is tumor grade; however, disease progression from a lower to higher grade can occur gradually over years or it may quickly transform into more aggressive forms. It remains unclear how this transition occurs and whether it may be correlated with therapeutic treatments or other factors.

Dr Ziv’s research was inspired by a colleague’s observations that higher-grade tumor cells were found interspersed in areas of low-grade tumor tissue. He began collaborating with colleagues studying evolutionary biology to use their algorithms to computationally ask whether and how tumors evolved from low grade to higher grade. 

“These tools have been used in pancreatic adenocarcinomas and lung adenocarcinomas, but no one has ever looked at this with neuroendocrine tumors and specifically the question of these high-grade neuroendocrine tumors,” Dr. Ziv says. 

As part of his NETRF-funded research, Dr. Ziv uses whole-exome sequencing over multiple time points to investigate this problem and has been surprised to discover that progenitors appear to contribute directly to high-grade tumors early on, rather than undergoing the expected linear progression toward high-grade tumors. 

Another aspect of Dr. Ziv’s NETRF-funded research involves investigating how different therapeutic treatments such as alkylating agents, radiation and embolizations affect the tumor grade changes that he is investigating. For example, Dr. Ziv notes that although alkylating agents can induce hypermutations, it remains unclear how these hypermutations influence the progression to higher, more aggressive tumor grades.

Dr. Ziv believes his research has already generated results suggesting mechanisms that are profoundly different from how he initially imagined neuroendocrine tumor progression. He hopes his investigation will form the basis of a much larger, multi-investigator project in the future that focuses on early identification and targeting of regions that can transform to high grade to further study and test the underlying bases of tumor evolution. 

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