Cancer cells often change their DNA to make more of the genes that help them grow and spread quickly. They do this with special proteins called transcription factors that read DNA, and helper proteins that change the DNA to work better. In prostate cancer cells, a protein called androgen receptor (AR) is the main cause of cancer growth. This is different from how AR works in normal prostate cells, where it helps the prostate develop properly and stops extra growth. We don’t know exactly how AR’s function changes in prostate cancer cells. My research tries to figure this out. With help from the V Foundation Award, my team will study a new protein called NSD2 that works with AR. Notably, NSD2 is only found in prostate cancer cells, not the normal ones. We’ll also test a new drug that stops NSD2 from working and see how well it kills cancer cells in different types of prostate cancer. This research will help us find more proteins that make AR cause cancer and create new medicines that target NSD2 to treat prostate cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Childhood brain tumors are a major cause of death for children. Medulloblastoma is one of the most common brain cancers in children and also one of the most difficult to treat. These children typically need extensive surgery, chemotherapy, and other treatments. Unfortunately, even with these treatments, many children with this cancer die from their disease. I am a pediatric neuro-oncologist, and it is my career hope to bring new therapies for medulloblastoma from the lab into the clinic.
My research studies why some children with medulloblastoma do not respond to treatment. I have made several discoveries that point toward new biology within the cancer cells that promote its growth. I have particularly focused on a new category of genes that we have recently described, called microproteins. These are small proteins that were missed in prior research on this cancer, and we have found that they are important for the ability for cancer cells to survive. I am optimistic that these discoveries are pointing towards new treatment options. To grow this vision, this V Foundation award will allow me to focus on studying certain new genes that we hope will lead to new treatments. Through this work, I hope to make new discoveries in medulloblastoma that are important for patients.
Brain cancers are typically fatal, even when patients undergo intensive treatment. While treatments have recently improved for many cancers, the last major treatment advance for glioblastoma (the most common aggressive brain cancer) was decades ago. Our research team is taking a new approach. We have discovered that aggressive brain cancers like glioblastoma often steal nutrients from the rest of the body. In this V Foundation-supported work, we will discover how brain cancers use these nutrients and whether blocking this nutrient uptake will slow brain cancer growth and improve treatment responses.
Funded by the Constellation Brands Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund
Ewing sarcoma is a cancer that is most often diagnosed in teenage children and young adults. There is a need for new therapies for this disease. The goal of our work is to develop new therapies for Ewing sarcoma focused on a drug target called EWS-FLI1. Multiple studies have shown that EWS-FLI1 is a promising drug target for this disease. In a clinical trial called SARC037, we are currently testing a combination therapy that we have shown targets EWS-FLI1. The goal of the current study is to try to understand why some patients in this trial respond to the therapy and others do not. To accomplish this, we will study ways that EWS-FLI1 resists targeting. We will identify molecular differences in tissue collected from patients who had an excellent response to the therapy compared to those who did not respond. In addition, we will test these differences in the laboratory to see how they impact sensitivity to the therapy used in SARC037. The results will guide future clinical studies that seek to target EWS-FLI1. In addition, they will provide insight into how EWS-FLI1 contributes to drug resistance to more traditional chemotherapy.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Diffuse midline glioma (DMG) is a fatal pediatric brain tumor, striking 200-400 children in the U.S. each year. Most children with DMG survive <1 year and have no proven therapies beyond radiation. A series of new drugs are being tested in clinical trials of DMG patients, but we lack sufficient tools to track how well they work. Cancer is a rapidly moving target as it can mutate to evade the onslaught of anti-cancer drugs; thus, tumors must be analyzed repeatedly during treatment to assess therapy response. Today’s standard of care for DMG is limited to frequent imaging (MRI), which provides insufficient data to assess therapeutic response. By advancing a new blood-based assay specific to DMG, we aim to dramatically improve our ability to track the effects of treatment on this devastating disease. We will exploit extracellular vesicles (EVs) — small “bubbles” shed by cells — as surrogate markers of therapy response in DMG patients. EVs contain molecular contents (e.g., protein, RNA, DNA) from their mother cells. Tumors shed large quantities of EVs into the bloodstream, offering a potential new way to monitor treatment in DMG patients. We will develop a new assay platform that integrates cutting-edge developments in materials, optics, and deep learning AI into a single system for efficient EV analysis and test whether our platform reliably predicts drug response in DMG patients. Our approach has the potential to transform DMG therapeutic trials and clinical practice, and its flexibility may lend itself to other types of pediatric and adult cancers.
The immune system is our body’s defense against cancer and other threats. Recently developed drugs enable a patient’s immune system to attack cancer and potentially destroy it. These drugsthat enlist the immune system have revolutionized cancer treatment. However, despitesuccesses, not all patients respond to these exciting new drugs. Cancers that do not respond tothese drugs are known as “cold” tumors because they prevent an attack by immune cells. Thisbreakdown occurs because many cell types must communicate effectively with one another foran immune response against cancer to occur – cancer disrupts this process. We will test whetherimmune cells can be improved, such that they are resistant to the miscommunication that cancercauses. Normally, immune cells use signals to communicate with each other. Cancer eitherblocks these signals or replaces them with ones that are misleading. Our goal is to restore thesignals needed by immune cells so that they can mount an effective and sustained attack againstcancer. To realize this goal we have developed activators of these signals. We will determinewhich of these signal activators can protect immune cells from being misled or disabled bycancer. Our long-term goal is to improve cancer treatment options by developing these signalactivators into new therapies that allow a patient’s immune cells to attack a cold tumor.
Funded by the Stuart Scott Memorial Cancer Research Fund
Immunotherapy has been one of the most remarkable advances in our fight against cancer. Its transformative impact on patients has been recognized with the 2018 Nobel Prize in Medicine. Immunotherapy, unlike other treatments for advanced tumors, can result in long term remissions and cures. Unfortunately, only a subset of patients benefit from immunotherapy. The majority of patients experience unremitting progression of cancer and a significant number suffer serious side-effects, which are sometimes life threatening. In those patients, immunotherapy could end up delaying or preventing other useful treatments. Cancer patients and their doctors badly need tests called ‘predictive biomarkers’ to determine whether a particular patient will benefit or be harmed by immunotherapy. Here, we propose to discover such biomarkers by analyzing tumor tissue samples from a large group of patients treated with immunotherapy. We have established a database (MIRIE) which includes all University of Michigan patients who received cancer immunotherapy since 2011. We have also developed a novel molecular assay (TAGTILE) to identify gene changes and gene expression patterns in their tumor tissues obtained before immunotherapy. By using TAGTILE to compare tumors from patients who did benefit from the therapy to tumors from patients who did not, we will be able to identify molecular characteristics of responding tumors. This information will be used to create a diagnostic test (e.g. a decision chart) to help oncologists and patients decide whether to choose immunotherapy. When routinely implemented, such a test can improve results in patients and avoid unnecessary side-effects.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Aromatase inhibitors (AIs) are important drugs for treating breast cancer. These drugs lower estrogen levels and reduce the chance that a woman will die from cancer. However, about one in five patients stops taking the drug early because of aggravating muscle and joint pain. Stopping the drug too soon can increase her risk of her cancer coming back. We do not know why women develop this pain, but it might be due to very low estrogen levels. We also do not know how to prevent the pain. Oxylipins are fat particles in the body that can increase or decrease pain. We believe that when a woman is treated with medicine that lowers her estrogen levels, that leads to more fats that cause pain. By also taking omega-3 pills, we believe that women instead will have more fats that decrease pain. This will allow her to continue to take the AI medication. To address this question, women who are starting to take an AI will also take either omega-3 pills or olive oil pills. We will ask if they develop pain and also check the levels of fats in their blood. Through this study we will find out if omega-3 pills prevent this side effect, and will learn more about how the AI medicine causes the pain. Knowing more about why women get this bothersome pain and how to prevent it will allow doctors to better treat patients and will allow more women to continue taking this life saving medication.
Diffuse large B-cell lymphoma is a blood cancer that is currently treated with chemotherapy drugs. These drugs can be toxic, and do not work for all patients. Certain cancer-causing genes must be turned on in order for lymphoma cells to grow and survive. One new way to treat patients with lymphoma might be to find drugs that turn off the ‘switches’ that cancer cells use to turn genes on. This could potentially kill cancer cells without hurting normal cells.
We will study the proteins and DNA code that serve as a ‘switch’ to control two lymphoma-promoting genes, MYC and BCL6. We will use new technologies to learn how these genes are turned on, and how we can block this process. Some lymphomas contain errors in the DNA code (mutations) that alter these gene ‘switches’. We will compare the function of lymphomas with mutations to lymphomas with intact ‘switches’.
This project has two main goals. First, we seek to create new tests that can be used to find mutated gene ‘switches’ and guide lymphoma patient care. Second, we seek to find target proteins that could be used to create new lymphoma treatments.
Leukemia stem cells (LSCs) are able to regenerate leukemia after chemotherapy and cause leukemia relapses. LSCs are transformed from the normal blood stem cells by mutations. We found that one of the commonly found mutations NRAS is able to re-program the signaling pathways in normal blood stem cells and chamge them into LSCs. Our studies showed that Nras does this through an unexpected pathway and targeting this pathway may lead to elimination of LSCs to potentially cure leukemia.
