Jason Sheltzer, PhD

Uncovering the role of aneuploidy in tumor development and progression

Aneuploidy is found in more than 90% of human tumors, but its effects on cellular physiology are poorly understood. While many methods exist to study genetic changes in individual oncogenes and tumor suppressors, our ability to model and interrogate chromosome-scale alterations is extremely limited. We are working to develop and apply a variety of technologies, including chromosome engineering, CRISPR mutagenesis, and single cell sequencing, in order to create new ways to study aneuploidy and better understand its consequences. Using these techniques, we have uncovered key roles for aneuploidy in metastatic dissemination, drug resistance, genomic instability, and several other cancer-related phenotypes.

Identifying cancer vulnerabilities and improving cancer therapies

The genetic alterations that occur during tumorigenesis re-wire the underlying architecture of cancer cells and create certain cancer “dependencies”: genes and pathways that are required for cancer cell growth but that are dispensable in normal tissue. Drugs that are designed to target these unique dependencies can serve as potent therapeutic agents. Using CRISPR, our lab has unexpectedly discovered that many targeted therapies that have advanced into clinical trials actually kill cancer cells independently of their reported targets. This pervasive mischaracterization of cancer drugs may partially explain why so many new oncology therapies fail during clinical testing. We are working to develop new techniques to identify cancer dependencies and characterize the activity of anti-cancer agents in order to improve clinical trial efficacy.

Characterizing CDK11 inhibition as a novel anti-cancer strategy

While studying mischaracterized cancer drugs, we recently discovered a small-molecule compound that exhibits potent and selective inhibition of the key cancer kinase CDK11. We subsequently demonstrated that CDK11 blockade has a unique molecular phenotype across a variety of cancer types. We are currently working to understand the function of CDK11 in normal and malignant cells, and to identify the cancer types most responsive to CDK11 inhibition.