Cancer treatments have improved over the past 30 years, but many patients still die from the disease. A new type of drug has been found that causes the patient’s body to attack the cancer. This new drug, called “immunotherapy”, works very well for some people but not for many others. Our studies try to find ways to make this treatment work for more patients. We are especially interested in how radiation can be used to improve immunotherapy and have found a new way that these two treatments work together. Our current work is focused on finding other ways that these treatments work together. We are especially interested in learning how we might improve how patients feel during and after treatment by reducing the side-effects of therapy. Overall, the major goal of our work is to increase the success of cancer treatment for all patients and to improve their overall quality of life.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Roger and Sally Krodel’s granddaughter, Angie Cerreta-Palauqui
Therapies to kill cancers typically get rid of the dividing cells. However, the few that remain are a mixture of resistant cells that can return later to form more tumors. This is a difficult problem to solve. My research looks into finding out which genes cancer cells choose to use when they are not dividing to repair their damaged DNA and survive. Our goal is to develop treatments that will interrupt those genes that cancer cells use so they can die. We also want to develop treatments that can not only work to stop many different types of cancers, but that can also work in combination with other therapies to block the return of cancers later in life. The potential long-term success of our research will help to ease the anxiety of cancer survivors by extending the cancer-free period indefinitely.
Funded by the Constellation Gold Network Distributors
My research is focused on understanding the role of genetic abnormalities in prostate cancer treatment resistance. Prostate cancer is one of the most common cancers in men, but what makes prostate cancer deadly in some men, but not others? The answer lies in the DNA of prostate tumor cells. Abnormal changes can occur in the DNA of tumor cells and give them the ability to resist standard treatments. Monitoring tumor DNA over time could uncover these changes. As the cancer progresses, tumor cells can move and grow in distant organs. Often, obtaining tumor cells from these organs is painful and difficult. What if tumor cells and its DNA were easier to access? We address this problem by using an exciting method, called a “liquid biopsy”, to measure tiny amounts of DNA that are released from tumor cells into the blood. We develop new computational techniques, combined with genetic sequencing, to reveal “signatures” of tumor DNA alterations from the blood. These signatures could allow oncologists to track whether a patient is responding well to treatment. They could also help predict whether a patient’s tumor has the potential to resist treatment. Ultimately our work will provide new tools to help doctors care for patients with less discomfort, more accuracy, and greater precision.
Funded by the Stuart Scott Memorial Cancer Research Fund
Ovarian cancer is one of the deadliest cancers among women worldwide. In 2019, nearly 22,240 new cases of ovarian cancer will be diagnosed in the US, and approximately 14,070 women will succumb to this disease. Most women respond well to the standard treatment, however, the majority of these patients (with estimates up to 75%) experience a recurrence of the disease due to acquired resistance of the tumor cells to chemotherapy.
This proposal is aimed at understanding what makes ovarian cancer cells resistant to therapy with the goal of discovering new avenues for therapeutic intervention. We will use state-of-the-art genome sequencing techniques to measure the changes that occur in primary ovarian tumor samples compared to recurrent tumor samples collected from the UNC Cancer Hospital. Our goal is to define how genes are being regulated in ovarian tumors in order to identify the molecular switches that are responsible for turning on genes that give rise to resistance. We hypothesize that these molecular switches (known as enhancers) are hijacked by the tumor cells for the activation of genes that give rise to resistance. We aim to identify their locations throughout the genome and determine which ones are responsible for drug resistance. Completion of this project will increase our knowledge about an understudied new facet of ovarian cancer, advance the way cancer research is conducted, provide a new set of biomarkers with diagnostic and prognostic potential, and highlight new targets for controlling cancer cell growth.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Rhabdomyosarcoma is the most common childhood cancer. Its most hard-to-treat subtype, fusion-positive alveolar Rhabdomyosarcoma (FP-ARMS), is mainly caused by chromosome translocations that form a “fused oncogene” called PAX3-FOXO1 or PAX7-FOXO1. Although the genetic mutations leading to FP-ARMS has been known for decades, the effective therapy to treat FP-ARMS patients is still lacking: less than 50% of the patients are cured, and patients survival rate is less than 10%. In FP-ARMS translocation, a piece of DNA is “fused” to another piece of DNA. Such fused DNA sequence not only consists of the protein-coding genes but also of the non-coding DNA sequences. These non-coding sequences used to be called as “junk DNA”, but more and more studies have shown that they play essential roles in human diseases, including cancer. However, in FP-ARMS, we know very little about whether or how the “fused” non-coding DNA sequences contribute to cancer. In this study, we will take advantage the newly developed technology to address this question that has never been asked: how the “fused” non-coding DNA sequences contribute to tumor development. Our work will help to understand the mechanism that control FP-ARMS development, and in the future, to provide new drug targets for better therapies. More importantly, since chromosome translocation is frequently observed in many childhood cancer types, our pioneer work will also establish the new methods that can be applied to study other pediatric cancers.
Funded by the Stuart Scott Memorial Cancer Research Fund
Normally, the cells of our body grow and divide only when needed. In cancer, however, this organization breaks down and cells grow out of control. Our lab studies signaling pathways that act as the cell’s circuitry and control when it grows and divides. We also study cellular metabolism, which consists of the chemical reactions a cell uses to turn nutrients into energy and cellular building blocks. Growth signaling pathways are often what become mutated and abnormally activated in cancer, in part, because they play important roles in controlling metabolism. We are particularly interested in a critical metabolic cofactor known as Coenzyme A, which is required to produce cellular energy and building blocks. We have gathered evidence that some cancer cells may have a greater need for Coenzyme A compared to normal cells. Therefore, it may be possible to kill certain tumors before damaging normal tissues by targeting Coenzyme A metabolism. We will characterize specific mutations that may make cells vulnerable to this treatment, and test this treatment concept in cancer cell cultures and mouse tumors. Our basic research into whether this treatment has promise is the necessary first step towards developing a potential new drug that may one day be used to successfully treat patients.
The most difficult challenge in treatment management of brain tumor patients is the need to accurately identify if a suspicious lesion on a post-treatment MRI scan is a benign treatment-effect or a “true” cancer recurrence. Both radiation effects and tumor recurrence have similar clinical symptoms and appearances on routine MRI scans. Currently, a highly invasive brain biopsy is the only option for confirmation of disease presence. Each biopsy procedure costs $20,000-$50,000/patient. Further, over 15% of patients who undergo biopsy will get an incorrect diagnosis due to difficulty in sampling of reliable locations of the tumor. There is hence a need for non-invasive image techniques to reliably differentiate benign treatment effects from tumor in brain tumor patients. Our team has developed new image-based biomarkers that use routine MRI scans to differentiate between these two conditions with an accuracy of 92% on n>200 studies. We propose to validate our image-based biomarkers in a limited clinical trial to reliably sample locations of tumor recurrence from benign radiation effects. The clinical trial will be based on creation of a “GPS” map of the locations of tumor and benign radiation necrosis in the tumor using MRI scans. This GPS map will assist neurosurgeons in reliably identifying locations to biopsy from during surgery. The proposed project, when successful, will thus have significant implications in personalizing treatment decisions in brain tumors.
Funded by the Dick Vitale Pediatric Cancer Research Fund
There is a unique group of cancers that progress quickly during childhood due to faults in the mechanisms which repair damaged DNA. As a result, these childhood cancers have the highest number of DNA mutations (hypermutant) of all human cancers. Immunotherapy has demonstrated hopeful results in these patients. Yet, 50% of these cancers will progress after initial response to immunotherapy. This poses a significant problem. Adoptive cell therapy takes advantage of using immune cells to kill cancer cells. Cell therapy has shown promising responses in many adult cancers. This effect is greater when cell therapy is used in combination with prior immunotherapy treatment. Our research team has developed new mouse models that successfully mimic these childhood brain cancers. One of the aims of our research project is to use these mouse models to study the role of cell therapy. We will determine overall survival and response to therapy. We aim to prove the feasibility of expanding childhood immune cells as a proof of concept through the use of our International Consortium. We will use complex computer software and genomic tools. These methods will provide a thorough review of immune cells. We will be able to predict which patients would benefit from cell therapy. This project will increase knowledge in this research area. In addition, it will answer important questions which will lead to improved patient outcomes and treatment options. Most importantly, this project will lead to the first-ever childhood cell therapy clinical trial.
Brain tumors cause the most cancer deaths in children. A tumor known as medulloblastoma (MB) is the most common type of childhood brain cancer. Children die of MB because the cancer spreads through the brain. New information indicates that some MB cells may first go into the bloodstream before spreading to the brain and forming new tumors. Cancer cells in the bloodstream are called “circulating tumor cells” (CTCs). We recently developed a tool called Cluster-Chip that can detect CTCs in the blood and remove them so that they can be studied. Using our Cluster-Chip tool, we want to see how often CTCs are found in the blood, and in which MB patients we find them in. Next, we want to see exactly what CTCs look like, what they are made of, and if they are different from the rest of the brain tumor. Finally, we want to see whether the number, the appearance or the make-up of CTCs in the blood can tell us if the tumor will go on to spread to the brain and if the patient will die of their disease. We will study 25 patients with MB and collect their blood at different times throughout their treatment. This information will help us to understand how MB cancer spreads and how to better treat MB tumor spread.
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.
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