All-Star Archives - V Foundation

Jeffrey Magee, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

My lab is working on new treatments for children with hard-to-cure cancers. We focus on a type of cancer called acute myeloid leukemia, or “AML” for short. AML accounts for about one-third of childhood leukemias. We have been less successful at treating AML than other childhood cancers. AML is challenging to treat because each patient may have different genetic mutations (alterations) causing their disease. A new drug that works for one patient might not work for another. Also, drugs that work in adult AML patients might not work well for childhood AML. To get around these problems, we create models that accurately reflect human childhood AML. We have created many different models to include the different types of mutations that patients can have. While studying these models, we discovered a protein called SPNS2 that might be a new drug target for tough AML cases. Early tests with an SPNS2 drug show promise in killing AML cells. This project aims to find out which patients will benefit most from SPNS2 drugs and see if combining these drugs with other AML drugs could improve treatment even further. We also aim to understand why SPNS2 is important in these cancers. My goals are to improve treatments and to broaden our understanding of AML in children.

Ulrich Steidl, MD, PhD

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.

Christina Curtis, PhD

Why do some people get certain types of cancer, while others don’t? For some cancers, we know that inherited genes play a role. But for many, it’s still a mystery. One reason is that cancer is very complex and we don’t fully understand how a person’s genetic makeup and immune system affects their risk.In our recent research, we found something surprising. We discovered that both a person’s genes and their immune system work together to influence which type of cancer they might develop. This includes hard-to-treat types like HER2+ and ER+ breast cancer, which can come back many years after treatment.Some early changes in a tumor’s DNA can act like a warning signal, helping the immune system find and destroy these abnormal cells before they grow. But if the tumor hides from the immune system, it can become more dangerous. That’s why it’s so important to find and treat these cancers early.Our work helps to explain the role of genetic variation in cancer, even when no single gene seems to be responsible. It also points to new ways to determine who is at risk and to create treatments that are personalized—based on each person’s genes and immune system. We’re working to turn these discoveries into better tools to predict, prevent, and treat cancer more effectively.

Chrystal Paulos, PhD

Melanoma is a serious and often deadly type of skin cancer. Although immunotherapy has saved many lives, it still doesn’t work for every patient. Our lab is developing ways to give the immune system another chance to succeed.We are creating a new kind of cell therapy using “helper” T cells, known as Th17 cells. These cells do more than attack cancer directly—they help guide and activate other immune cells, turning the fight into a team effort.We discovered that a molecule called ICOS helps these helper T cells survive longer and build immune memory. This memory may help stop cancer from coming back in the future.Our goal is to turn this finding into a new treatment for people with melanoma who did not respond to standard therapies. By helping the immune system work better, we hope to offer patients more than extra time. We want to offer lasting hope.This research moves us closer to making melanoma a disease we can truly overcome.

Yuxuan Miao, PhD

More people are getting head and neck cancer caused by the human papillomavirus (HPV). Traditional treatments like surgery or radiation can cause strong side effects. Sometimes, the cancer comes back. Because of this, doctors are looking for safer and better ways to treat these cancers. Immunotherapy is a newer treatment. It helps the body’s immune system find and destroy cancer cells. Some people with head and neck cancer do well with a type of immunotherapy called “immune checkpoint inhibitors.” But, patients whose cancer is caused by HPV usually do not benefit as much. A new immunotherapy called HB-200 is being tested. It is designed to help the immune system better find and attack cancer linked to HPV. Early studies show that HB-200 may work for patients with HPV-positive cancer, even if other treatments have not helped. Our research looks at tumor samples from people with and without HPV. All of these patients received different types of immunotherapy. We are using simple lab tests and special tools to learn why HPV-related cancers do not respond well to older treatments, but do respond to HB-200. Our goal is to make HB-200 better and find new ways to treat these cancers. We hope this will lead to better care and longer, healthier lives for patients.

Todd Fehniger, MD, PhD

Cancer immunotherapy is a medicine that helps the body’s immune system fight cancer. One type, called “CAR T cells,” changes immune cells so they can see and attack cancer better. This has been a big help for people with serious lymphoma, but it can cause strong side effects like bad flu symptoms, brain problems, and low blood counts.This project is trying a new kind of immunotherapy that uses different immune cells called “natural killer cells.” We found a way to make these cells remember how to fight cancer better. These “memory natural killer cells” have helped leukemia patients without causing strong side effects. But there are still problems, like having a hard time seeing all types of cancer (including lymphoma) and being stopped by a “brake” on their surface. Natural killer cells also need a special growth signal called interleukin 15 to stay alive and fight cancer well.This project will fix these problems by adding tiny “mini” proteins to the memory natural killer cells. These changes will help them attack tough lymphoma, remove the “brake,” and make their own growth signal. We hope this will create a new treatment for difficult lymphoma and help us find more ways to make natural killer cells better in the future.

Agnel Sfeir, PhD

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.

Diana Hargreaves, PhD

Pancreatic cancer (PC) is a leading cause of cancer death in America. PC has few treatment options. Immunotherapy is a treatment that has promise. Immunotherapy can cure cancer, but it has never worked for PC. We found that some PCs respond well to immunotherapy. These patients have a mutation in a SWI/SNF gene. We began a trial to test how SWI/SNF mutant PCs respond to immunotherapy. We will collect blood to see what changes with treatment. We will make mice with SWI/SNF mutant cancer and test if these mice respond to immunotherapy. We will also test if blocking SWI/SNF with a drug can make tumors respond to immunotherapy. We hope to identify PC patients that can benefit from immunotherapy. We will also identify new treatments for PC that may help other patients.

Kyle Payne, PhD

Ovarian cancer is one of the deadliest types of cancer and has very few treatment options. However, there is hope that new types of treatment that help the body’s own immune system fight cancer could help patients live longer. Scientists have found that ovarian cancer patients who have more T cells—special immune cells that can find and kill cancer—often survive longer than patients with fewer T cells. But we still don’t fully understand what T cells are targeting when they attack ovarian cancer cells. This lack of knowledge has slowed down the development of better immune-based treatments for this disease. Our study is trying to solve this problem. Using new technology, we plan to discover what T cells are looking for when they fight ovarian cancer. We also want to create a new treatment that helps T cells better find and kill cancer cells. To do this, we will use a method called mass spectrometry to find targets on the tumor cells. Then we will use computer tools and lab tests in animal models to see if T cells can recognize and respond to those targets. If this approach works, we will move forward with a clinical trial to test if the new treatment helps ovarian cancer patients live longer. We also believe this work could lead to new treatments for other types of cancer.

Lewis Chodosh, MD, PhD

Breast cancer comes back in up to 30% of patients, sometimes many years after treatment. These recurrences cause nearly all deaths from the disease. The returning cancer comes from tiny “sleeper” cells that survive treatment. These cells stay in the body without growing, in a resting or dormant state.

If we can keep these cells from “waking up,” we may be able to stop breast cancer from coming back and save lives. In our earlier research using mouse models and patient samples, we found something surprising: breast cancer sleeper cells can change their behavior and start acting like bone-forming cells. This change may help keep them dormant and stop the cancer from returning. We also showed that this bone forming activity can be seen in animals using PET scans—a common imaging method used in hospitals.

Our project aims to build on this discovery and develop a new way to keep sleeper cells dormant. To do this, we will:

Study this bone-forming process in patient tumor samples under the microscope.
Improve how we detect the bone forming process using PET scans in animal models.
Use what we learn to design a clinical trial that looks for whether this process occurs in patients during treatment.

If successful, our work could reveal a new way the body keeps cancer cells asleep, help us find which patients are affected, and lead to new treatments to prevent breast cancer from returning.