North Carolina Archives

Justin Milner, PhD

Pancreatic cancer remains one of the most difficult cancers to treat. There is a clear need for more effective therapies. CAR-T cell therapy has shown promise in some cancers. However, pancreatic tumors create a harsh environment that weakens T cells and limits how they work. This project aims to reprogram T cells so they can persist and continue fighting in these conditions.T cells can be genetically engineered. This allows us to adjust the instructions that control how they behave. Most current approaches focus on removing barriers, like taking the brakes off. In this project, we take a different approach. We aim to strengthen T cells so they can better adapt and function within tumors.Our goal is to identify changes that make T cells more potent and longer-lasting. These insights will enable more effective CAR-T therapies for pancreatic cancer and other solid tumors.

Trudy Oliver, PhD

Some cancers are very hard to treat because they grow fast and stop responding to therapy. One example is a group of tumors called tuft-like cancers. These cancers can form in several organs, including the lung. Patients with these tumors often have few treatment options, and the disease can progress quickly.Our research focuses on finding a new way to treat tuft-like cancers. Our lab discovered a drug target that appears to be very important for the survival of these cancer cells. Early studies show that blocking this target can slow tumor growth in laboratory models.This treatment may also help the body’s immune system fight cancer. In other words, hitting this target may deliver a “one-two punch.” The drug could weaken the tumor while also helping immune cells attack it.In this project, we will study how this target helps tuft-like cancers grow and survive. We will test drugs that block it in models that closely resemble human cancer. We will also study patient tumor samples to learn how these cancers interact with the immune system.Our goal is to move this discovery closer to clinical trials. If successful, this work could lead to the first targeted treatment for tuft-like cancers and give new hope to patients facing this aggressive cancer type.

John Hickey, PhD

T cell therapy uses a person’s own immune cells to fight cancer. It has cured some blood cancers, like leukemia and lymphoma. But it does not work well for solid tumors in organs such as the lung, pancreas, or colon. My research asks why—and how to fix it.One problem is how the cells are grown before they go back into the body. Today, most labs use a “one size fits all” recipe. That recipe helps T cells multiply, but it does not train them for the tough job inside a solid tumor. Another problem is that people are different. Age, sex, and health history can change how T cells grow and work. A third gap is knowledge: we do not fully know what these cells do once they enter a tumor.To solve these challenges, I am building new tools to fine-tune how T cells are prepared and to track how they work in tumors. I will test many preparation methods at the same time and combine advanced imaging and AI to find the best recipes that make T cells that get into tumors, last longer, and fight cancer cells more effectively. The goal is simple: smarter, stronger T cell treatments for solid tumors. If successful, this work will guide doctors to match the right recipe to each patient and cancer. That could mean better responses, fewer side effects, and longer lives.

Corinne Linardic, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Rhabdomyosarcoma (RMS) is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood. RMS can be classified as lacking or having a PAX3::FOXO1 fusion, in which part of the PAX3 protein becomes attached to part of the FOXO1 protein. This hybrid, fused protein is the driving mutation of fusion-positive RMS (FP-RMS). Survival for children with FP-RMS is less than 30%, and this has not improved in over 40 years. In fact, we have no new effective drugs for this cancer. Chemotherapies developed in the 1970s are still the best we have today. This research focuses on understanding how to block PAX3::FOXO1. However, PAX3::FOXO1 is a difficult drug target due to its complex structure. To complicate matters, at least six other fusions have recently been discovered that drive FP-RMS. Rather than being discouraged, we have leveraged this information. We have figured out that all of these seven fusions depend upon a core set of helper proteins to cause FP-RMS. In this project we will figure out the regions of the seven fusions that have common roles and that are responsible for recruiting the helper proteins. Last, we will use hi-tech chemistry to find small molecules to attach to these common regions to dissolve away the helper proteins. This will provide a platform from which to design, and in the future, clinically evaluate new drugs to block any fusion found in FP-RMS. We hope to provide targeted, less toxic treatments.

Jessica Thaxton, PhD, MsCR

Funded with support from the Scott Hamilton CARES Foundation

T cells are part of the body’s immune system. T cells ward off disease but are also capable of fighting cancers. In fact, immune therapies in cancers have produced major gains in allowing patients with cancer to survive long-term. T cells can invade cancers, but cancers create a hostile environment that limits T cell killing capacity. This makes immune therapies function poorly. We have discovered a pathway in T cells that is engaged by the hostile environment of tumors that induces T cell distress and death. We have found a group of drugs that inhibit this pathway. These drugs also protect T cells from sensing the stressful environment of cancer. This group of drugs allows T cells to live longer and fight harder to eliminate cancer. We have found that these drugs improve the long-term outcomes of immune therapies and hold potential to increase the number of patients cured of cancer when treated with immune therapy. This project plans to study this stress pathway in T cells in samples from patients with cancer and to test these drugs in several models so that they can be used in the clinic to fight cancer in patients.

Jessica Sun, MD

Funded in partnership with the Pediatric Cancer Research Foundation through the 2024 Dribble for Victory

Clinical trials help improve the treatment of children with cancer. But, it takes a lot of work to be able to offer clinical trials to patients. This grant will help us add another person our research team part-time. This person will gather information about clinical trials and share it with patients, families, and other providers so that people know what we have available at Duke. They will work with other doctors at Duke who treat children and young adults with cancer to make sure we are all offering clinical trials to our patients. They will also follow up with survivors of pediatric cancer to let them know of any available research options. By doing these things, we hope to be able to offer clinical trials to more patients.

Kris Wood, PhD

Funded by the Orr Family Foundation

Lung cancers are often discovered after they have spread throughout the body. When this happens, patients must be treated with drugs. These drugs often shrink tumors but do not cure patients. The tumor cells that survive these drug treatments are known as “residual” cells. Residual cells eventually grow back, causing death. For this reason, we are very interested in discovering drugs that can kill residual lung cancer cells. Recently we discovered that residual lung cancer cells cannot survive without an enzyme called PKN2. We have access to a drug that blocks PKN2. Further, we already know that this drug is safe for patients. We are applying for grant funds to do three things. First, we will determine which residual lung cancers are most sensitive to this drug. Second, we will determine how this drug kills residual lung cancers. Third, we will determine how well this drug prevents lung cancer from relapsing in mice. Together, these studies will advance our understanding of residual lung cancer. They will also advance a new drug therapy that can be quickly translated to clinical trials by our team of expert doctors and scientists.

Stephanie Wheeler, PhD, MPH

Funded by the 2024 Victory Ride to Cure Cancer

The Southeastern American Indian Cancer Health Equity Partnership (SAICEP) is a team made up of three cancer centers in North Carolina. These centers are working together to help lower cancer rates in American Indian communities. This year, with help from the V Foundation, SAICEP is starting a new project for Native youth and young adults, ages 16 to 30. The goal is to lower the risk of cancer by focusing on three things: getting the HPV vaccine, staying safe in the sun, and stop the use of unsafe tobacco products. To do this, SAICEP will work with the North Carolina Native American Youth Organization (NCNAYO). They will choose and train Native youth to become health ambassadors. These ambassadors will share important health information in their communities. SAICEP will also go to Native events across the state to talk with people and hand out materials about cancer health. At the end of the project, they will ask the youth and others what they learned and how the project helped. This project will help more young Native people stay healthy and avoid cancer in the future. It also gives Native youth a chance to lead and help their own communities.

Alicia Darnell, PhD

Funded with support from Hockey Fights Cancer powered by the V Foundation presented by AstraZeneca

Cancer cells are always growing, and they need nutrients to keep up this fast growth. An exciting idea is that we might be able to starve cancer cells without harming healthy cells by getting rid of nutrients that cancer cells need. A drug being developed right now called ADI-PEG20 destroys a nutrient called arginine, which is an amino acid that is used to make protein and is particularly important for cancer cells. My lab studies what happens when cancer cells don’t have enough arginine. We want to understand how ADI-PEG20 works, how to improve it, and which cancers to treat with it. We have found that restricting arginine disrupts ribosomes, the machines that build new protein, causing them to get stuck and abandon their jobs early. We want to study three things to figure out how this impacts ADI-PEG20 treatment. First, why is protein production in cancer cells so sensitive to arginine levels? Next, what machinery in the cell is responsible for causing “starved” ribosomes to press the eject button in the middle of doing their jobs? Finally, what effect does this have on a cancer cell? This work will help us understand how a nutrient like arginine can directly control very important processes in the cell like protein production. It will also reveal how we can take advantage of cancer’s dependence on arginine to shrink tumors.

Kathleen Mulvaney, PhD

To understand how genes change in cancer, our field has uncovered many gene mutations and deletions in patient tumors. However, we have not yet been able to create treatments that can combat many of these changes. This research proposal will test the potential for new combinations of medicines to treat tumors with a common gene many cancers need on for survival, PRMT5. A number of aggressive tumor types have PRMT5 as a drug target including lung cancer which remains the leading cause of cancer-related deaths in the U.S. and pancreatic cancer where >90% of patients with this disease will succumb to it. We need to make better medicines to treat these cancers.

We will test our ability to drug PRMT5 protein in lung tumors in combination with other new drug targets. This work will provide fundamental insights into mechanisms of PRMT5 function and reveal new strategies to treat an aggressive and deadly form of cancer. It is necessary that we test and design effective, rationale combination therapies in cancer. These efforts aim to effectively kill tumors and to avoid tumors coming back in the patient.

This work could lead to clinical trials in the future that would directly benefit cancer patients and their families. My goal is for our laboratory to contribute to mentoring young scientists and to improving cancer treatment for patients. This V scholar award will help me to achieve my goals by providing additional support, mentorship, and scientific exchanges.