Cancer-associated cachexia — the severe muscle wasting seen in many cancer patients — affects roughly half of all people with cancer and accounts for nearly 30% of cancer deaths. It robs patients of strength and mobility, undermines their ability to tolerate treatment, and shortens survival. Despite this, no FDA-approved treatments exist.

The Baylies Lab studies cachexia using fruit flies engineered to develop intestinal tumors — a powerful model for uncovering the biology behind this condition. A key finding centers on Impl2, a tumor-secreted protein that rises early in disease and tracks closely with the first signs of metabolic and muscle dysfunction, well before any visible wasting occurs. This positions Impl2 as a potential early warning signal rather than simply a consequence of advanced disease. The team also found that selectively reducing insulin signaling in muscle produced an unexpected benefit: flies outperformed controls, pointing to a protective adaptive response — known as mitohormesis — that may be therapeutically exploitable.

Applying micro-CT imaging across the whole body revealed the full scope of damage as disease progressed. Muscle volume drops early but structural damage builds steadily within muscle tissue, and later stages bring deterioration in reproductive organs and signs of neurodegeneration in the brain. Strikingly, the timing and severity of all these effects differed between male and female flies, revealing that cachexia does not follow a single uniform course.

Collectively, these findings reframe cachexia as a dynamic process shaped by both disease stage and biological sex — and point toward the need for sex- and stage-aware approaches in both research and, ultimately, clinical treatment.

Antibody-drug conjugates (ADCs) have transformed cancer treatment by delivering potent therapies directly to tumor cells. However, their effectiveness is often limited by toxicity to healthy tissues, restricting the doses that patients can safely receive.

Dr. Cheung's laboratory is developing a novel platform known as Self-Assembling and DisAssembling Antibodies (SADA), designed to improve the precision of drug delivery while reducing exposure to normal organs. By combining SADA technology with the powerful anti-cancer drug deruxtecan, the team created a series of next-generation drug conjugates engineered to selectively target tumors and enhance therapeutic efficacy.

Their studies demonstrated effective tumor targeting and identified new molecular designs that improve drug delivery and cellular uptake. The researchers also established a flexible platform that can be adapted to different cancer types and therapeutic payloads.

This research advances a promising new approach to targeted cancer therapy, with the potential to increase treatment effectiveness while minimizing side effects for patients.

Mutant IDH enzymes drive cancer by producing 2-hydroxyglutarate (2HG)—a metabolite that disrupts normal gene regulation and locks cancer cells in a stem-like state. While IDH inhibitor drugs can induce durable responses in some patients, fewer than half benefit, and resistance inevitably develops.

Rather than inhibiting mutant IDH, Dr. Intlekofer's team pursued a counterintuitive strategy: hyperactivating the enzyme to overwhelm cancer cells with toxic levels of 2HG. Using genetic models, metabolic profiling, and large-scale chemical screening, the researchers demonstrated that excessive 2HG production selectively impairs the growth and survival of IDH-mutant cancer cells while exposing previously unknown metabolic vulnerabilities.

The team also identified promising compounds capable of increasing mutant IDH activity and uncovered key pathways that influence sensitivity and resistance to this approach. This Geoffrey Beene-supported research provides a mechanistic foundation for developing a new class of therapies that exploit the metabolic weaknesses created by IDH mutations and may ultimately improve outcomes for patients with IDH-mutant cancers.

High-fat and high-fructose diets can trigger chronic liver inflammation, known as non-alcoholic steatohepatitis, or NASH, which significantly increases the risk of liver cancer. Yet the biological steps that connect dietary fat, inflammation, and cancer remain poorly understood.

Dr. Benezra’s research focuses on ID1, a protein found to be elevated in Kupffer cells, the resident immune cells of the liver, in response to high-fat dietary stress. His team discovered that removing ID1 can strongly protect against the inflammatory response that follows fat accumulation in the liver, pointing to a new mechanism driving NASH progression.

This project investigates how ID1 controls liver inflammation and whether targeted nanoparticle delivery of an ID1-degrading therapy can reduce NASH and prevent progression to hepatocellular carcinoma. By targeting the immune cells that help fuel liver inflammation, this work could open a new path toward preventing diet-associated liver cancer before it develops.

NRF2 is a powerful cancer-driving transcription factor that helps tumor cells survive oxidative stress and resist treatments such as chemotherapy and radiation. Although NRF2 is activated in many solid tumors, including liver, lung, and gastrointestinal cancers, it has remained extremely difficult to target directly with drugs.

Dr. Wendel’s team is taking a different approach: instead of trying to inhibit NRF2 itself, they are identifying the proteins that NRF2 depends on to function. Their research uncovered an upstream kinase for NRF2, a kinase that appears to activate NRF2 and help cancer cells maintain their stress-protection program.

The breakthrough potential lies in making an “undruggable” cancer driver targetable by attacking one of its critical regulators. By testing this upstream kinase for NRF2 inhibitor in NRF2-driven cancer models, this project could lead to new strategies for weakening tumor defenses, overcoming treatment resistance, and improving outcomes for patients with aggressive solid tumors.

Leptomeningeal metastasis occurs when cancer spreads into the spinal fluid-filled space surrounding the brain and spinal cord. It is a devastating and often fatal complication of cancers such as breast cancer, lung cancer, and melanoma, and it remains extremely difficult to study because patient-derived leptomeningeal cancer cells have historically failed to grow in the laboratory.

Dr. Boire’s research focuses on the most lethal form of these cells: “floating” cancer cells that move freely in the cerebrospinal fluid and are associated with more aggressive disease. Her team is working to recreate the unique leptomeningeal environment in the lab by identifying the specific metabolic and signaling conditions these cells need to survive.

The goal is to build the first robust culture system for patient-derived leptomeningeal cancer cells, enabling large-scale drug and genetic screens that are not currently possible. This work could accelerate therapeutic discovery for a devastating form of metastasis that urgently needs new treatment options.

Cancer cells must continuously rewire their metabolism to support rapid growth. Dr. An’s research focuses on mTOR, a master regulator of cell growth, and a newly discovered role it plays in cancer metabolism: controlling the stability of critical metabolic enzymes.

Rather than focusing only on how cancer cells turn genes on or off, this project investigates how cancer cells preserve or destroy the enzymes they need to keep producing fuel and building blocks for growth. The breakthrough concept is that tumors may sustain their metabolism by dynamically controlling enzyme stability through the cell’s protein-disposal system. Understanding this process could reveal new vulnerabilities in cancer metabolism and point toward strategies that disrupt tumor growth at its source.

B cells protect the body by producing antibodies capable of recognizing an enormous range of pathogens. To create this diversity, B cells deliberately alter their DNA through processes called class switch recombination and somatic hypermutation. When these DNA-altering programs go awry, the immune system not only fails mount an immune response against invading pathogens, the risk of B cell lymphomas also increase.

Dr. Chaudhuri’s research examines how activation-induced cytidine deaminase, or AID, acts not only on antibody genes but also on other regions of the genome, including genes involved in immune communication. The key breakthrough is a new view of AID activity: rather than being merely an accidental source of DNA damage associated with pathology, it may also help regulate B cell function after infection or vaccination. This work could deepen our understanding of normal immunity while revealing how the same processes can contribute to B cell cancers.

Diet can influence cancer progression, but the biological mechanisms behind this connection remain poorly understood. Dr. Li’s research focuses on how diet-conditioned tumors interact with macrophages, immune cells that can either support or suppress tumor growth depending on their environment.

This project investigates how macrophages recognize and restrain metabolically active tumors driven by cMyc, a powerful cancer-promoting gene. The breakthrough focus is the possibility that diet can shape tumor-immune crosstalk in ways that make cancers more vulnerable to immune attack. By identifying how macrophages suppress the growth of these tumors—and exploring ways to enhance that response pharmacologically—this research could he

Head and neck cancer is a major global cause of cancer death, and many patients develop aggressive disease that is difficult to treat. Dr. Morris’s project focuses on HPV negative head and neck squamous cell carcinoma.

This research investigates how loss of tumor suppressor genes in head and neck cancer may change cancer cell metabolism, helping tumors grow more aggressively and/or metastasize more easily. This  work also developed further a novel mouse model of head and neck cancer, which could identify new vulnerabilities in a large group of cancers and point toward more effective strategies for patients whose tumors currently lack targeted treatment options.

Radiation therapy is a cornerstone of cancer treatment, but its effects may extend beyond directly killing tumor cells. Dr. Paul Romesser's research investigates how radiation can push cancer cells into a state called senescence, in which they stop dividing and release signals that reshape the immune response.

The breakthrough idea is that radiation-induced senescence may transform tumors into powerful stimulators of anti-cancer immunity. Dr. Romesser's work seeks to understand how this process contributes to both local tumor control and immune responses at distant tumor sites, and whether it can be enhanced through targeted inhibition of DNA damage repair. By studying both laboratory models and patient tissue, his team is advancing new strategies that could make radiation therapy more effective by harnessing the body's own immune system to fight cancer.

Tumors are not made up of identical cancer cells. Even within the same tumor, individual cells can behave differently, adopt distinct molecular states, and respond differently to therapy. This diversity is a major reason treatments fail: some cancer cell populations survive and allow the tumor to regrow.

Dr. Tammela’s project focuses on hypoxia, or low oxygen, as a potential driver of this cell-state diversity. The key goal is to understand how oxygen-deprived regions of tumors influence what cancer cells become and how they respond to treatment. By identifying the forces that shape tumor composition, this research could point to a new generation of therapies designed not only to kill cancer cells, but to control the cellular makeup of tumors and make them more responsive to treatment.

FOXA1 is a pioneer transcription factor, meaning it helps open regions of DNA so that other gene-regulating proteins can act. While FOXA1 plays an important role in normal development, it is also recurrently mutated in prostate and breast cancer.

Dr. Leslie’s research, conducted in collaboration with Charles Sawyers, investigates how cancer-associated FOXA1 mutations rewire the regulatory landscape of tumor cells. Using prostate cancer organoid models and single-cell multiome profiling, her team found that oncogenic FOXA1 mutants can gain abnormal pioneering activity, changing which regions of DNA become accessible and altering the behavior of cooperating factors such as hormone receptors. The work could reveal how disrupted transcriptional networks drive cancer and identify mechanisms relevant to multiple hormone-driven and transcription-factor-driven tumors.

Although many children with cancer are cured, much of that success still depends on intensive chemotherapy, radiation, and surgery. Newer targeted and immune-based therapies have had less impact in pediatric cancers than in adult cancers, leaving a major need for safer and more effective treatments for children and young adults.

Dr. Kung’s project brings together investigators across MSK to develop next-generation engineered T cell therapies for pediatric sarcomas and acute myelogenous leukemia. The breakthrough goal is to apply advances in cell engineering to cancers such as osteosarcoma, Ewing sarcoma, and AML, where new therapeutic approaches are urgently needed. By combining expertise across multiple projects and shared technology cores, this work aims to accelerate the development of immune therapies that could improve outcomes while reducing reliance on highly toxic conventional treatments.

Prostate cancer often depends on androgen receptor signaling, and therapies that block this pathway are highly effective at first. Over time, however, treatment resistance can emerge, and some tumors transform into neuroendocrine prostate cancer, an aggressive form that no longer responds well to hormone therapy or chemotherapy.

Dr. Lewis’s project targets DLL3, a protein believed to be highly expressed on these resistant neuroendocrine prostate cancer lesions. His team is developing fully human DLL3-targeting antibodies that can be used to create diagnostic and therapeutic radiopharmaceuticals. The breakthrough goal is to use the same target to both find and treat aggressive tumors that currently have few effective options. This radiotheranostic strategy could provide a new path forward for patients with advanced prostate cancer that has escaped standard therapies.

Mutations in SF3B1 are defining events in myelodysplastic syndromes, a group of blood disorders that can progress to aggressive leukemia. While SF3B1 mutations may initiate disease, additional mutations often determine whether the disease remains stable or transforms into a more dangerous form.

This project uses Geoffrey Beene support to establish a panel of genetically matched induced pluripotent stem cell lines from patients with SF3B1-mutated MDS. These models allow researchers to compare mutated and non-mutated cells from the same patient background, providing a powerful way to study disease evolution. By integrating genomic, transcriptomic, and epigenetic profiling, the work aims to uncover the mechanisms that drive progression and identify therapeutic vulnerabilities before MDS transforms into acute leukemia.

CAR T cell therapy has produced remarkable responses in patients with leukemia and lymphoma, including some whose cancers returned after multiple rounds of chemotherapy. However, CD19 CAR T cell therapy can also cause severe and sometimes life-threatening toxicities, limiting where and how broadly this powerful treatment can be used.

Dr. Park’s project investigates whether early intervention with anakinra, a drug that blocks the inflammatory cytokine IL-1, can prevent or reduce CAR T cell-associated side effects. The breakthrough goal is to make CAR T therapy safer without compromising its cancer-fighting power. If successful, this strategy could help expand access to CAR T cell therapy, allowing more patients to benefit from one of the most promising advances in modern cancer treatment.

Natural killer cells are immune cells that can rapidly recognize and destroy cancer cells. Among patients treated with stem cell transplantation, acute myeloid leukemia is one of the cancers most readily targeted by NK cells, making these cells an important focus for improving anti-leukemia immunity.

Dr. Sun’s research investigates how IRF8, a key transcriptional regulator, controls NK cell responses against AML. The central breakthrough goal is to understand the genetic program that enables NK cells to recognize and eliminate leukemia cells effectively. By defining how this program works, the project could reveal ways to strengthen NK cell activity after transplantation or in future immune-based therapies. This research may help harness the body’s innate immune system to improve outcomes for patients with AML.