Cold Spring Harbor Laboratory
Our research focuses on drug target discovery. We are using high-throughput genetic screens to discover novel surfaces on oncoprotein that are essential for sustaining the aberrant properties of cancer cells.
Our goal is identify novel routes for targeting fusion oncoproteins in
leukemia and sarcomas, which are major causes of pediatric malignancies.
Chris graduated with a degree in biochemistry from Penn State University and subsequently earned Ph.D. (2005) and M.D. (2007) degrees from the University of Pennsylvania. His dissertation research was performed in the laboratory of Gerd Blobel, where he studied basic mechanisms of long-range enhancer function, hematopoietic transcription factors, and histone lysine methylation. In 2008, Chris accepted a position as a Cold Spring Harbor Laboratory Fellow and during this time, he initiated research into how chromatin modifications support the pathogenesis of leukemia. A key focus of this work has been to use functional genomics approaches to reveal unique chromatin regulator dependencies in cancer cells. This has 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 therapeutic target in acute myeloid leukemia. This work has also revealed novel mechanisms of transcriptional regulation, such as identifying a role for MLL as a mitotic bookmark and a role for TRIM33 in enhancer decommissioning. Chris is the recipient of a Leukemia and Lymphoma Society Scholar Award and the 2015 AACR Outstanding Achievement Award.
CRISPR-scanning as a tool for cancer therapeutic discovery and validation
One of the guiding principles of modern cancer therapy is to use ‘smart’ drugs that target aberrant proteins that exist in tumor cells, but which do not exist, or are irrelevant, in normal cells. This approach has been transformative in the treatment of a small number of cancers, in which highly effective drugs with limited side effects selectively interfere with a protein ‘chimera’, that is, a protein that is an inappropriate fusion of two otherwise normal proteins.
“This generous award will allow us to aggressively pursue basic research into the molecular mechanisms that cause pediatric cancers.”
Protein chimeras represent some of the most powerful drivers of human cancer, which are often by themselves enough to initiate and sustain the disease after multiple rounds of chemotherapy. While there are a few examples of successful drugs that target protein chimeras to treat cancer, the unfortunate reality is that most of these aberrant fusion proteins have yet to be successfully targeted in a direct manner. One major obstacle in developing protein chimera-targeting therapeutics is our limited molecular knowledge of how these cancer-causing proteins operate in the cell. My laboratory has recently developed a novel technique for ‘scanning’ proteins to reveal all of the key molecular details for how they can cause a cancer. There are many advantages of this technique over other traditional approaches for studying how a protein works, which we seek to exploit to gain fresh insights into how protein chimeras initiate and sustain human cancer. This research may spawn novel tactics for undermining the activity of cancer-causing proteins and may guide the development of next-generation cancer therapies.
“I would define innovation in biology research as any deviation for the path well-traveled, irregardless of whether it leads to short-term biomedical benefit.”