Turning Cancer's Genetic Chaos Against Itself

An All-Star Translational Award from the V Foundation for Cancer Research will help advance a promising therapeutic strategy developed at the Herbert Irving Comprehensive Cancer Center (HICCC) that challenges decades of conventional thinking about how the immune system recognizes cancer. 

Benjamin Izar, MD, PhD, the Vivian and Seymour Milstein Family Associate Professor of Medicine and a member of the Tumor Biology and Microenvironment (TBM) program at the HICCC, is among the latest recipients of the V Foundation's Translational Grant, which supports high-impact discoveries with a clear path toward improving patient care. The award will accelerate development of a first-in-class therapy designed to treat cancers driven by chromosomal instability, a hallmark of many aggressive tumors that is associated with metastasis, treatment resistance, and poor outcomes.

Rethinking how cancer evades the immune system

Chromosomal instability (CIN) is one of cancer's most powerful survival mechanisms. As cancer cells continually gain and lose large pieces of DNA, they rapidly evolve, allowing tumors to spread, develop resistance to therapies, and evade the immune system. 

For years, researchers have sought ways to disrupt this process, but the underlying biology remained poorly understood. 

Izar's laboratory asked a fundamental question: if normal cells that acquire large-scale DNA errors are quickly recognized and eliminated by the immune system, why doesn't the same thing happen in cancer cells living in a perpetual state of genetic chaos? 

The answer, his team discovered, overturned a long-standing assumption in the field. 

Rather than inhibiting the immune system from sensing DNA damage, chromosomally unstable cancer cells chronically activate the very immune sensors meant to eliminate them. Over time, these sensors become overwhelmed and effectively shut down. Instead of alerting the immune system to danger, cancer cells exploit this exhausted state to remain hidden while continuing to evolve. 

For years, many researchers believed this immune pathway should be stimulated to strengthen anti-cancer immunity. Izar's team found the opposite. Because the pathway is already chronically overactivated in these tumors, further stimulation only reinforces its dysfunctional state. Instead, temporarily inhibiting the pathway allows it to reset, restoring the immune system's ability to recognize chromosomally unstable cancer cells. 

It's like a car engine that's revving in neutral. The harder you press the gas pedal, the quicker the engine burns out. Our approach is to let the gas pedal off, allowing that engine reset so it can once again do what it was designed to do.

Building on this discovery, the laboratory developed a first-in-class therapeutic compound that targets this newly identified vulnerability. Rather than simply attacking the tumor directly, the drug exploits cancer's own biology, turning the very process that drives tumor evolution into its greatest weakness. 

Importantly, once the pathway is restored, cancer cells begin producing immune-stimulating cytokines and inflammatory signals that recruit immune cells into the tumor, effectively transforming cancers that once escaped immune detection into targets for immune destruction. In essence, the therapy turns cancer against itself. 

From discovery to drug development

The V Foundation award will support the next phase of development, including optimization of the therapeutic compound and the preclinical studies needed to prepare an Investigational New Drug (IND) application with the U.S. Food and Drug Administration. 

Much of that groundwork has already been completed at Columbia. Through support from the Irving Cancer Drug Discovery Program, the Izar laboratory established key steps in the drug development process, including developing the lead compounds, creating sophisticated laboratory assays, and generating humanized mouse models capable of testing the therapy in an intact immune system. The new V Foundation grant will move the initial work forward into preclinical and eventually, clinical studies. 

"Our goal is to bring this as fast as possible into the clinic," Izar says. "We've already completed much of the foundational work, and this grant will help us take the next critical steps toward clinical translation."

Building on years of discovery

The recent V Foundation award builds on a growing body of work from the Izar laboratory that has reshaped understanding of how chromosomal instability fuels cancer evolution. Through a series of influential studies, the team has demonstrated how chromosomal instability drives immune evasion, metastasis, and treatment resistance across multiple tumor types, laying the scientific foundation for the new therapeutic strategy now moving toward the clinic. Izar’s earlier work was also supported by an Abeloff V Scholar award in 2020. 

While Izar’s initial work has focused on melanoma, liver cancer, breast cancer, and lung cancer, the same biology appears to extend across many solid tumors. Early studies have already shown promise in gastroesophageal cancers and sarcomas, raising the possibility that this strategy could ultimately benefit patients with a broad range of difficult-to-treat cancers.