GRANTEE: Christopher Vakoc, MD, PhD
Cold Spring Harbor Laboratory
Research Project: Enhancer Reprogramming as a Driver of Pancreatic Cancer Progression
Award: 2016 The Daniel and Janet Mordecai Foundation – Pancreatic Cancer Action Network – AACR Career Development Award
Award Period: July 1, 2016 – June 30, 2018
After graduating with a degree in biochemistry from Penn State University, Dr. Vakoc earned PhD (2005) and MD (2007) degrees from the University of Pennsylvania. In 2008, he accepted a position as a Cold Spring Harbor Laboratory (CSHL) Fellow through a program that allows young scientists to pursue independent research before taking a faculty position. During this time, Dr. Vakoc initiated research into how chromatin modifications support the pathogenesis of leukemia. Chromatin is a complex mixture of proteins and DNA, and its regulation is critical for the expression of genes that code for proteins involved in cellular growth, survival, etc. This work led to the identification of several chromatin regulator pathways that are essential to maintain the leukemia cell state, which includes the discovery of BRD4 as a drug target in acute myeloid leukemia. Dr. Vakoc is currently an associate professor at CSHL.
In normal cells and cancer cells, genes encoded by DNA lead to the production of proteins through a highly regulated process called transcription. Transcription is mediated by factors that induce the expression of specific genes. Proteins that are transcribed from genes cause key cellular functions – growth, survival, movement – that are present in normal cells and dysregulated in cancer cells.
Within DNA, particular regions, called enhancers, serve as sites for transcription factor binding and activation, leading to protein expression. To better understand enhancer sites in pancreatic cancer, Dr. Vakoc and his colleagues study organoids, or three-dimensional colonies of cells grown in the laboratory. The research team was surprised to observe that organoids derived from metastases (sites of cancer spread) had many abnormalities within their enhancer regions – much more than were present in organoids derived from primary tumors of the pancreas.
To further understand this discovery, Dr. Vakoc proposes to determine how transcription factors influence enhancer sites within metastatic pancreatic cancer cells as compared to primary pancreatic cancer cells and healthy pancreas cells. He will study instances where enhancer alterations lead to the increased expression of genes as well as cases where the abnormalities suppress the expression of genes that are termed tumor suppressors, or genes that code for proteins that function to prevent cancer initiation. The goal of this project is to ascertain whether the activity of transcription factors can be modified to stop or slow pancreatic cancer cell growth or prevent metastatic spread.