State: New York

Our immune system has special cells called T cells that can recognize and attack cancer. Even though these tumor-fighting cells are often present, many tumors still grow because T cells stop working properly during cancer development. Cancers can be grouped into two main types based on how the immune system responds. Some are called “hot” tumors. In these cancers, T cells are able to enter the tumor, but the tumor environment weakens them so they cannot kill cancer cells. Other cancers are called “cold” tumors which comprise approximately half of all human cancers. In cold tumors, T cells are mostly missing from the tumors. Cold cancers do not respond well to immune-based treatments. Scientists still do not fully understand why T cells fail to enter cold tumors or why these cancers resist treatment. To study this, we created preclinical mouse models in which tumors grow naturally and show cold immune phenotypes. Using these models, we found that tumor-fighting T cells are present in nearby lymph nodes but do not move into the tumor. Over time, these T cells become resistant to immune treatments, which is linked to the loss of important genes needed for T cell function. In this project, we will study in mice and patients with cancer why T cells get stuck, fail to enter tumors, and stop responding to treatment. This research may lead to new ways to make immunotherapy work for patients with immune-cold cancers.

Myelodysplastic syndromes (MDS) are a group of blood cancers that cause low blood cell counts. The most common problem is anemia, which means the body does not have enough red blood cells. This can make people feel very tired and often leads to the need for blood transfusions.In MDS, the bone marrow (where blood cells are made) shows higher levels of inflammation. The cells in the bone marrow produce proteins that increase this inflammation in the body. In this project, we aim to reduce inflammation by targeting a key system called the inflammasome. The inflammasome is a group of proteins that helps to produce a substance called IL-1beta, which can make the disease worse.We are studying a new drug called HT-6184 in our lab. This drug helps block the inflammasome and reduce inflammation. In early lab tests, it has lowered inflammation and increased red blood cell levels.In this study, we will first identify the proteins and cells that cause increased inflammation in MDS. Then, we will test ways to block these targets using antibodies and specific drugs in lab-grown cells and patient blood samples. Most importantly, we will test how well the inflammasome-blocking drug works in MDS blood samples and in mouse models of the disease. This drug has already been approved by the FDA for clinical trials.If our results are successful, this research could help move this drug quickly into clinical trials designed for patients with MDS.

Cancer cells often live in a state of genetic chaos. This makes them hard to kill with existing drugs and allows cancer to spread to other parts of the body. We wanted to find out why this happens so we could stop it. We discovered that this chaos helps cancer cells hide from the body’s immune system. Usually, the immune system finds and kills cancer cells, but these cells stay invisible. To fix this, we created a new medicine. It targets the chaotic cancer cells but does not affect healthy cells. This drug turns the cancer against itself. Instead of hiding from the immune system, the cancer cells now send out a signal. This signal tells the immune system to come and destroy them. We are now testing this new medication on different types of cancers that are otherwise difficult to treat. If it works, it could lead to new treatments that save many lives.

Funded by the Dick Vitale Pediatric Cancer Research Fund

Cancer immunotherapy is a treatment that helps the body’s immune system fight cancer. It works very well for some cancers, but it is less effective in infants and children. One reason is that the young immune system is built to turn down strong reactions. This helps babies avoid harmful inflammation when they first eat food or meet the friendly bacteria in their gut. The Brown Lab recently found a new type of immune cell, called Thetis cells. These cells play an important role in suppressing immune responses during early life. We think they may also train the immune system not to attack cancers, which lets tumors grow. In this project, we will study how Thetis cells act in childhood cancers such as hepatoblastoma and use what we learn to design new treatments.

Acute Myeloid Leukemia (AML) is a fast-growing blood cancer that is very hard to treat. Fewer than 20% of patients live more than five years after being diagnosed. One big problem is that AML often comes back after treatment or stops responding to chemotherapy, which is the main reason people die from this disease. Most research has looked at genetic changes that help cancer cells resist treatment, but new studies show that non-genetic changes also play an important role.Our research focuses on one of these non-genetic factors called “transcriptional noise.” This means natural changes in how genes are turned on and off in cells. Using advanced tools that look at single molecules, we found that chemotherapy causes a quick increase in this transcriptional noise. This seems to help leukemia cells survive the treatment. When we blocked this noise—by targeting an enzyme called Pol II that controls gene activity—the leukemia cells became more sensitive to chemotherapy. We saw this in lab tests and in mouse experiments. We also found that certain “early response” genes—genes that react fast to chemotherapy—show a lot of this noise, which means they could be new targets for drugs. Our future research will try to figure out exactly which genes are involved, how this noise helps cancer resist treatment, and which types of AML can be treated better by blocking transcriptional noise. This new approach could lead to better ways to stop drug resistance in AML and other cancers, giving patients hope for more successful treatments in the future.

Cells use DNA repair systems to fix damage and keep their DNA stable. When these systems fail, it can lead to cancer and make treatment harder. One toxic type of damage is a double-strand break (DSB), where both strands of DNA are cut. In healthy cells, DSBs are usually fixed by a process called homologous recombination (HR). This method is very accurate. Some tumors, especially those with BRCA1 or BRCA2 mutations, lose the ability to use HR. These tumors rely on backup repair methods that are less accurate. One of these is called microhomology-mediated end joining (MMEJ). MMEJ fixes breaks by using short, matching DNA sequences, but it often adds or deletes small sections of DNA.MMEJ depends on an enzyme called polymerase theta (Polθ), which is found at high levels in many cancers. Research shows that BRCA-deficient tumors need Polθ to survive. Because of this, Polθ is now being tested as a drug target, alone and with PARP inhibitors. This project studies how MMEJ helps cancer cells resist treatment. We focus on two key ways. First, MMEJ can create changes that fix BRCA1 or BRCA2, which restores HR and reduces the effects of PARP inhibitors. Second, MMEJ may support the growth of extra circular DNA (ecDNA) that carries cancer genes. This makes tumors grow faster and resist therapy. By understanding how Polθ drives these changes, we hope to find new ways to treat cancer and make current therapies last longer.