The Schug laboratory is interested in understanding the way a cancer feeds itself in order to support its growth. The amounts and types of foods that cancers consume can be very different from the ones that our bodies normally use. For this reason, we believe that these differences can be used as new targeted treatment options for cancer patients. We have identified a specific food that is uniquely used by cancers to fuel their growth. Our goal is to create drugs that can block cancer’s ability to feed on this food. In addition, we are exploring the idea of combining this drug with other available treatments to improve patient survival. This research is important because it looks to block behaviors that are unique to cancer and therefore spares the body from harmful side effects. Furthermore, our results suggest that this food source is used by nearly all types of cancer. Because of this, we believe that our research is likely to make a major impact on the lives of many different cancer patients.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a common cancer in children and adults that does not respond well to regular chemotherapy medicines and often comes back. We found in earlier studies that Ph-like ALL has ‘miswired’ signaling networks inside its cells. These networks seem to be very sensitive to targeted medicines called kinase inhibitors. We are now testing one of these inhibitor medicines with chemotherapy in children with Ph-like ALL in a clinical trial, but we do not yet know if adding this new medication will be better than regular chemotherapy by itself. We will study leukemia cells from patients treated on this clinical trial to try to answer this question. We will also use specialized mouse models made from the children’s leukemia cells to understand what other miswired networks happen in Ph-like ALL and could be attacked by new medicines. These laboratory studies will help us to learn if using several inhibitor medicines together could be even better than current chemotherapy. If this is the case, then we will then hope to test this new treatment idea in children with Ph-like ALL in future clinical trials.
Approximately 80,000 Americans will be diagnosed with bladder cancer in 2019 and 18,000 will die from their disease this year. Recent studies show that bladder cancer cells often carry a high number of genetic mutations which correlate with anti-tumor immune responses. New drugs known as immune checkpoint inhibitors (ICI), have produce dramatic clinical responses in up to 25% of bladder cancer patients, by enhancing anti-tumor immune responses that help control the tumor. However, despite intense efforts, biomarkers that predict response to ICI remain elusive. Furthermore, the mechanisms responsible for resistance to ICI are unknown. Predicting which patients respond to ICI would enable responders to be streamlined to receive ICIs, and resistant patients to receive alternative or combination therapies to improve their outcome. Pet dogs also develop bladder cancer that shares similar clinical, biological and genetic features with human bladder cancer. Despite standard of care treatment, most dogs will die of their disease within one year of diagnosis. Here we will investigate the genetic mutational burden in canine bladder cancer and determine whether it also correlates with tumor immune profiles. We will develop a canine ICI that can be used therapeutically in dogs with bladder cancer and we will determine whether effective ICI therapy is associated with enhanced anti-tumor immune responses and which factors or combination of factors predict ICI response. This work aims to establish the dog as a valuable model for human bladder cancer, provide a novel treatment for these dogs and guide biomarker discovery for humans.
Hormone therapy medicine helps lower the chance of breast cancer growing or coming back. African American breast cancer survivors say they lack information about hormone therapy. Women also say that side effects are a main reason for stopping hormone therapy. We are doing a study that will test a text message program for these women. Women who join the study will be randomly assigned to one of two groups. One group will get text messages and the other will not. The text messages have information to help women deal with side effects. We think the women getting texts will have fewer side effects and greater belief they can manage hormone therapy. We also think they will understand why hormone therapy is important. We think this will help women worry less about hormone therapy and continue taking it. With the V-Foundation funding, our main goal is to increase the number of women who join the study. We will use our current partnership with community members and social media to recruit more women. This is the first study to test a text message program for African American women on hormone therapy. It is also one of the first to use a community partnership and social media to recruit women.
Funded in partnership with WWE in honor of Connor’s Cure
Brain cancer is now the leading cause of cancer deaths in children. A tumor known as high-grade glioma (HGG) is the deadliest type. Children with HGG are treated with surgery, chemotherapy, and radiation. They often enroll in clinical trials to try new treatments. Unfortunately, most children die within two years of diagnosis. Part of the problem is that HGG tumors develop ways to resist the effects of treatments. Our recent work using promising new glioma treatments has identified a pattern of steps that glioma cells use to develop treatment resistance. Using state-of-the-art genetic testing, we saw how HGGs at first responded to new therapies but then became resistant. Resistant HGGs showed increased levels of a protein called QPRT, which can use energy metabolites like NAD+ to protect cancer cells from the therapy designed to kill them. This suggests that by stopping the protein function, we could overcome treatment resistance. We want to achieve two aims: First: to see if QPRT is active in other commonly used treatments for HGG, and also if recurring childhood HGGs typically show high QPRT levels. Second, using tumor tissue that we cultured in the lab, we identified a drug that inhibits the NAD+ pathway and reverses treatment resistance. We want to test this drug in an animal model of treatment-resistant HGG to see if it can prolong survival. Together these aims would reveal a way that HGGs resist treatment and potentially show how a drug could block this action to overcome treatment resistance in these tumors.
Black Americans often do not take part in research. They also have more aggressive breast cancer and a higher death rate from breast cancer. Overall, clinical trials have led to better outcomes for patients with breast cancer. However, the lack of Black Americans in clinical trials may be one explanation for higher death rates because new treatments are not tested in their aggressive cancers. Our goal is to help the community learn more about the role of research in breast cancer, and the value of taking part in that research. We will work with trusted members of the Black American community through our partners and lay Community Ambassador (CA) program to plan three forums. At these forums, community members will be able to talk with our doctors, clinical research coordinators, and CAs to learn about breast cancer, clinical trials, and what it means to take part in research. The forums will focus on breast cancer research. They will include questions from a host as well as questions from the audience. This will allow for an open discussion about breast cancer research. The goal of the forums will be to raise participants’ knowledge about research, and increase their odds of taking part in research.
Funded in partnership with WWE in honor of Connor’s Cure
Medulloblastoma is the most common malignant brain tumor in children. There are four distinct forms of this tumor based on its gene profiles, and a form known as Group 3 medulloblastoma is the most aggressive and deadly, which accounts for 25%-30% of all medulloblastoma. Each medulloblastoma group has distinct abnormal gene expression that determines how it creates, grows, and spreads tumors. Changes in gene behavior, like overexpression or underexpression, are controlled by what is called epigenetics. Fortunately, we know how to manipulate epigenetics with drugs. Dr. Hu and his colleagues found two epigenetic components that play important roles in controlling gene expression in tumor. Interestingly, these two epigenetic components seem to work together: when one component is suppressed, the other increases, and vice versa. A gene called MYC is very active in many cancers including Group 3 medulloblastoma. In this project, Dr. Hu’s team will characterize these two epigenetic components to understand more precisely how they work, particular in controlling MYC expression, even further, they will test in the lab whether “drugging” these epigenetic factors can halt the growth and spread of medulloblastoma tumors. If this hypothesis is proven, it may be possible to use these drugs in combination to treat this devastating childhood cancer.
Metastasis is the spread of cancer to one or more different organs of the body from where it started. The brain is one of the common organs for cancer recurrence. Even with aggressive treatments, brain metastasis is increasingly becoming a significant clinical problem. To find new therapeutic targets to treat brain metastasis, we need to first understand the progression of the disease.
Metastases are generally site specific. The environment of each organ is different. Cancer cells may only be able to colonize one or more specific organs, depending on the primary tumor from which the cells derive. As illustrated in the ‘seed and soil’ theory, tumor cells behave like seeds that can only successfully colonize selective organs that offer the right soil for their survival and growth. Thus, we plan to understand brain metastasis by focusing on the complex conversation between cancer cells (the seed) and brain cells (the soil). Using advanced microscopy techniques, we will directly visualize the metastatic brain tumors in the living animals. Meanwhile, we will detect therapeutic responses when newly designed treatments are applied. From these studies, we will obtain dynamic longitudinal changes in the cancer cells and the surrounding brain cells. This will allow “reconstruction” of the brain metastasis process, as well as therapeutic response. We strongly believe that these studies will yield new ways of fighting brain metastasis.
Over the past several decades, there has been a steady increase in cure rates in children with the so- called B-cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer. Yet many B-ALL patients who failed the initial chemotherapy still die from their disease. Five years ago many of these high-risk patients began to benefit from immunotherapy, whereby patients’ own immune systems are trained to recognize and destroy the leukemic cells. One common form of immunotherapy is based on recognition of CD19, a protein residing on the surface of most leukemic cells. However, even this breakthrough treatment fails in about a third of patients, suggesting that other leukemia proteins need to be targeted in parallel. One alternative protein target is called CD22. CD22-directed immunotherapies show promise, but are not without their own record of failures. Our previous studies led us to believe that one common cause of treatment failure is improper assembly of the CD22 protein, resulting in re-shuffling of its key parts called ectodomains. This re-shuffling could result in CD22 becoming unrecognizable to the immune system. On the other hand, improperly assembled CD22 could be targeted using a new type of immunotherapeutics, which are trained to recognize improper junctions between ectodomains. The proposed work will test these ideas using leukemic cells grown in Petri dishes and in mice and samples from ongoing clinical trials. It will also extend our current studies to other cell surface proteins. In the end, the TVF-funded work would lead to a more precise matching of future patients to best possible treatments and thus much better outcomes.
Funded by the Stuart Scott Memorial Cancer Research Fund
Lung cancer is the main cause of death in the world. For unknown reasons, African Americans (AA) have more aggressive lung cancer compared to Caucasians. Recently, immunotherapy demonstrated that one out of five of patents have tumor shrinkage. Long term remissions are happening in one out of seven lung cancer patients. This is very exciting, but combinations of 2 or 3 immunotherapy drugs are needed to cure more patients.
We proposed the lung cancer treatment combination that can block tumor blood vessel growth, and boost immune system. We think that this combination approach will cure more lung cancers. We will soon start a clinical study combining two immunotherapy drugs. One out of four patients on our study will be AA. We hope to find immune or blood vessel growth related markers to help predict who would benefit from this drug combination. This can help to use the right drugs for the right patients. In this study, we also plan to investigate why AA have more aggressive lung cancer.
In Aim 1, we will perform detailed analysis of blood proteins and white cells from the blood of patients participating in our study. In Aim 2, we will correlate genes and other markers with response to immunotherapy combination. In Aim 3, we will compare blood proteins and tissue gene levels between AA and Caucasians.
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