For 80+ years, chemotherapy has been critical for treating cancer—but it comes with a brutal tradeoff. These drugs work, but they’re not well-tolerated, causing severe side effects that force doctors to use lower, less effective doses. The result? Tumors evolve, treatments fail, and patients suffer.

Dr. Lareau is using generative artificial intelligence to fundamentally change this equation. His team is designing chemotherapy-binding proteins (CBPs)—custom-engineered molecules that sequester chemotherapy drugs away from healthy tissue while maintaining their cancer-killing power at the tumor site. Using cutting-edge protein design tools like AlphaFold2, they’re creating programmable solutions that could work across multiple tumor types and drugs, unlocking safer and more effective dosing for already-approved therapies.

The goal: Make existing chemotherapy safer and more effective without developing new drugs.

Your DNA is constantly under attack – from environmental damage, replication errors, and normal cellular processes. When DNA breaks, your cells have an elegant repair system called homologous recombination. But what happens in the final stages of this repair process can mean the difference between a perfectly fixed gene and a cancer-causing mutation.

Drs. Jasin and Zhao are investigating these critical late-stage repair mechanisms to understand how cells ensure faithful DNA repair outcomes. Using a combination of biochemical and cellular approaches, they’re determining how several DNA repair factors work together to clear repair intermediates—the molecular scaffolding left behind during the repair process.

Understanding these mechanisms is essential for genome maintenance and preventing the mutations that lead to cancer.

How do cancer cells gain new abilities, such as growing faster or resisting treatment? One way is through focal genomic amplification, in which cancer cells make extra copies of specific DNA regions. These extra copies can increase the activity of cancer-driving genes or regulatory elements, helping tumors adapt and survive.

Dr. Choi is developing a molecular recording platform to study how these amplifications arise and influence tumor evolution. His approach uses genome editing to program targeted amplifications while recording each cell’s lineage and environmental signals, allowing researchers to reconstruct how cancer cell clones change over time.

Using lung adenocarcinoma as a model, this work will examine amplification of the NKX2-1 super-enhancer and its role in tumor growth, cell identity, and resistance to EGFR-targeted therapies. This research could reveal how genetic changes and environmental pressures work together to drive cancer progression.

This research lays the groundwork for understanding tumor growth and treatment resistance at a fundamental level.

Chronic hepatitis B virus (HBV) infection remains a leading cause of liver cancer worldwide because the virus establishes a persistent reservoir of DNA that can evade treatment and remain in cells for decades. Dr. David’s research seeks to understand how this viral DNA is organized and regulated—and how those mechanisms can be disrupted.

Her team discovered that HBV DNA adopts a highly structured chromatin architecture that controls expression of HBx, a viral protein essential for maintaining infection. Most notably, they demonstrated that the small molecule CBL-137 can selectively remodel this viral chromatin, suppress HBx expression, and destabilize the viral reservoir. These findings identify a promising new therapeutic strategy for targeting chronic HBV infection and provide a foundation for preventing the liver cancers that can arise from long-term viral persistence.

Pancreatic ductal adenocarcinoma is among the deadliest cancers, with few effective treatment options and a five-year survival rate below 15%. Dr. Lewis and his team are developing innovative radiotheranostic approaches that combine targeted imaging and therapy to improve the precision and effectiveness of treatment.

The researchers engineered novel antibody-drug conjugates designed to deliver radiosensitizing agents directly to pancreatic tumors, making cancer cells more vulnerable to radiation while limiting damage to healthy tissues. After overcoming challenges with an initial design, they developed a next-generation platform that demonstrated strong tumor targeting and imaging performance in preclinical models. This work has already led to a patent application and lays the groundwork for a new class of precision therapies that could improve outcomes for patients with pancreatic cancer.

Activating mutations in the signaling protein RAS are found in approximately 25% of cancers. RAS and many other proteins must be connected to the plasma membrane of cells to enable their signaling capacity and to drive cancer progression. The RAS converting enzyme I (RCE1) catalyzes a preparatory step (proteolysis) in a pathway known as prenylation that anchors these proteins to the plasma membrane. Inhibition of RCE1 may be a strategy to intervene in cancers bearing mutations in RAS. RCE1 catalyzes its reaction in another membrane, that of the endoplasmic reticulum, but how it does so is a mystery. Dr. Long’s team seeks to address this mechanistic question by determining three-dimensional cryo-EM structures of RCE1 alone and in complex with substrates, products, and inhibitors. The insights may lead to advances in inhibitor design.

Glioblastoma is the most aggressive form of brain cancer, fueled by cancer stem cells that can survive treatment and drive tumor recurrence. Dr. Parada’s research seeks to understand how epigenetic programs control the transition of these stem-like cells into the diverse tumor cell populations that make glioblastoma so difficult to treat.

Using sophisticated genetic models and epigenetic profiling, his team identified molecular signatures that distinguish stem-like and proliferative tumor states and uncovered regulatory factors that may govern the transition between them. These findings provide new insight into how glioblastoma evolves, adapts, and resists therapy. By revealing the mechanisms that sustain cancer stem cells, this work may help identify new therapeutic vulnerabilities capable of preventing recurrence and improving outcomes for patients with this devastating disease.

Immunotherapy has transformed cancer treatment, yet many patients fail to benefit because immune cells become dysfunctional within the hostile environment of the tumor. Dr. Vardhana’s research explores how nutrients regulate the function of immune cells, and how changes in their availability within tumors weakens the ability of the immune system to recognize and destroy cancer cells.

His team discovered that one particular family of micronutrients, amino acids, become limited within tumors, and impair the ability of tumor infiltrating T cells to produce the cytotoxic proteins that are required for immunotherapy to be effective against cancer. Building on this finding, his group has identified strategies that restore T-cell function by improving both the uptake and utilization of amino acids, while also developing new approaches to enhance the release of proteins required for effective anti-tumor responses. These studies reveal fundamental mechanisms underlying immunotherapy resistance and point toward new ways to strengthen the immune system’s ability to fight cancer.

This funding supports state-of-the-art new detector arrays for mouse body and mouse brain for the Small Animal Imaging Core’s 7T MRI scanner. Currently, researchers can perform MRI scan only one mouse at a time—a major bottleneck for large preclinical trials. With this new technology, up to 4 mice can be scanned simultaneously.

Impact: Dramatically increased capacity and speed for in vivo tumor MRI screening, accelerating therapeutic trials across multiple research projects.

DNA sequencing is fundamental to cancer research—revealing the causes and potential cures for cancer. At IGO we run several complex laboratory workflows that utilize different PCR cycling programs. However, PCR is a process that should be minimized where possible to reduce sequencing artifacts. The iconPCR instrument from n6 TEC will monitors and minimizes PCR cycling, reduces the need for multiple instruments, and enables high quality data production compared to standard PCR instruments.

Impact: Enhanced efficiency and data quality for the MSK genomics facility, supporting discoveries across all cancer research projects.