All-Star Archives - V Foundation

Hanna Mikkola, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Children with Down syndrome have a higher chance of getting blood cancer called leukemia. Many babies are born with a condition called transient abnormal myelopoiesis (TAM). TAM starts before birth and causes too many immature blood cells to grow. In most babies, TAM goes away on its own. But in some, it can be very serious or later turn into leukemia. Right now, doctors do not know why this happens or how to tell which babies are at risk.In this study, we will use new tools to look at single blood cells to learn more about how TAM starts, how it changes into leukemia, and why treatments sometimes stop working. We will study blood and bone marrow samples from children at different stages of the disease, as well as from pregnancies with Down syndrome, to find out when and where the first changes begin.Our goal is to find better ways to predict which babies with Down syndrome will get leukemia and to develop safer, more effective treatments. This work could improve survival and quality of life for children with Down syndrome and their families.

Raymond Moellering, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Burkett’s lymphoma and neuroblastoma are two different types of childhood cancers that share a common link: the MYC gene. Chemotherapy is often used for treatment, but the side effects can be hard on young patients. Doctors and researchers now know that the side effects are mostly from blocking the growth of both cancer cells and healthy cells. Chemotherapy also does not work well for some patients. Our research focuses on drugs that target MYC to safely slow the growth of cancer cells. We will test these new drugs in the laboratory for future development into medications for patients. In the end, our work will produce better medicines to treat these cancers without giving up patient comfort.

Chrysothemis Brown, MD, PhD

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.

Uri Tabori, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund

When the body is unable to fix damaged DNA, it can cause some childhood cancers to grow very quickly. These cancers have many DNA changes (called “mutations”) so we call them “hypermutant”. Some children are born with a syndrome, called CMMRD, which makes them develop a lot of these hypermutant cancers at a young age. A treatment called immunotherapy has shown positive results in these patients. However, it doesn’t work for everybody and when a cancer is found late, about 40% of children will get worse, even after treatment. Immunotherapy can also cause side effects, some of which are serious. Recently, we discovered that mRNA-LNP vaccines (similar to those used for COVID-19) may actually be able to prevent cancers in children with CMMRD. These vaccines have very few side effects and might help many patients. However, we still need to learn more about what components make an effective vaccine and then test it in human and animal models. In this project, we will do three things. We will first determine what should be included in a vaccine to make it work well. We will then test the vaccine in mice to see if it can prevent cancer. Finally, we will see how well the vaccine works and how safe it is for humans. To do this, we will work with international collaborators who have experience making vaccines. This work has the potential to help children with many other cancer-causing syndromes, as well as common adult cancers.

Kenneth Westover, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Many children with cancer have changes in their genes that help tumors grow. One important change is called FGFR1 N546K, which is found in about 3% of children with solid tumors, including certain brain cancers and other childhood cancers. This change makes cancer cells grow faster, but current cancer drugs do not work well against it.Our research team will search for new medicines that specifically target this genetic change. We will begin by testing 65,000 compounds to find which ones block the cancer-causing protein. The most promising compounds will then be tested in cancer cells to confirm they work in the right way. Finally, we will study how these medicines attach to the protein using detailed imaging, which will guide us in improving them further.Children with this gene change currently have very few treatment options. If we are successful, the medicines we discover could help treat not only one type of cancer but many different childhood cancers that share similar gene changes. Our ultimate goal is to give doctors new tools that help children live longer, healthier lives and to create a path toward better treatments for childhood cancer.

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.

Markus Müschen, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Many children survive with current treatments but when the disease recurs, it is often deadly and as such we need new treatment options for these children.In most cancers, a protein called beta-catenin is highly prevalent, making cancer cells grow faster. We thought this would be true for ALL but found the opposite. In ALL, beta-catenin is kept at very low levels because the cells quickly break it down. When it does appear, it works with a partner called LEF1 instead of its usual partner, TCF7. This pair slows cancer growth and can even make the cells die.This means ALL cells are very sensitive to beta-catenin buildup. We can use this weakness to our advantage. We have found four kinds of existing drugs, already tested in people for other diseases, which block the breakdown of beta-catenin in different ways.Our goal is to test these drugs to see which works best against ALL that does not respond to chemotherapy. Because these drugs are already known to be safe, we can move faster toward clinical testing in children. If successful, this approach could give new hope to families facing relapsed leukemia.

Evan Weber, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Pediatric cancer patients have greatly benefited from CAR-T cell therapy, which is a treatment that uses a child’s own T cells – a type of immune cell – to find and kill cancer. This approach has helped many children with blood cancers, but fewer than half stay cancer-free after one year. One reason for this is that sometimes CAR-T cells don’t survive long enough in the body to stop the cancer from returning. To fix this issue, we are trying to develop ways to make CAR-T cells act more like marathon runners that stay in the fight instead of sprinters that slow down too soon.My research focuses on the bone marrow, which is the part of the body where some blood cancers hide and where CAR-T cells go to fight them. We’ve found that the bone marrow sends out special signals that affect how well CAR-T cells survive. In this project, we will study those signals and use what we learn to create longer-lasting CAR-T cells. This work could ultimately make CAR-T therapies work better for kids and adults and inform other approaches to help these powerful immune cells stay active longer.

Andras Heczey, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Special white blood cells can be engineered to fight cancer. They are engineered with a molecule call CAR. This molecule helps them kill cancer cells. The special white blood cells include T and NK cells. These cells can cure some blood cancers. They show great promise for children with solid tumors. CAR T cells often get exhausted in solid tumors. CAR T cells are currently made outside the body. This can further weaken them.Our research aims to overcome these challenges. We will target Glypican-3 (GPC3). It is a molecule found on many childhood solid tumors. We propose a new way to engineer CAR T cells inside the body (in-body). We will use special virus-like particles (LVPs). These LVPs will precisely reprogram the children’s own immune cells to fight GPC3-positive cancer. We will test “armoring” strategies of CAR T cells. This is to make these in-body generated CAR T/NK cells even more powerful and long-lasting.Our hypothesis is that in-body engineered GPC3-CAR T cells will be highly effective against cancer cells. We will first maximize the effectiveness of our LVP delivery system. Next, we will compare the different armoring strategies. We will study how they boost the survival of in-body generated CAR T cells. Finally, we will select the most potent armoring strategy. Ultimately, this research aims to bring safer, more effective CAR T-cell therapy to children with solid tumors. The findings may be applicable to other cancers in the future.

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.