Grant Archive - Page 43 of 138

Hector Franco, Ph.D.

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.

Yarui Diao, Ph.D.

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.

Christian Dibble, Ph.D.

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.

Pallavi Tiwari, Ph.D.

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.

Uri Tabori, M.D.

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.

Tobey MacDonald, MD

Funded by the Buster and Kristen Posey Fund

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.

Sarah Tasian, M.D.

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.

Agata Smogorzewska, M.D., Ph.D.

Vintner Grant funded by the V Foundation Wine Celebration in honor of Joe and Pat Harbison

DNA, which stores all of our genetic information, is constantly being damaged by environmental sources such as sunlight or from products of normal processes within each cell. If unrepaired, DNA damage may result in mistakes, which can lead to cancer. We study human cells from patients who do not have the full capacity to repair the DNA due to a genetic disease called Fanconi anemia. They are predisposed to the development of cancers including those of head and neck. We propose to determine how cancers develop in this group of patients by identifying all the permanent changes that occur in Fanconi anemia tumors and to study how these changes lead to cancer development. We also want to take advantage of these changes to find better treatments for head and neck cancers. For our work, we use patient tumor samples and mouse models of cancer. In addition to all of the tools we currently have at our disposal, we aim to develop new ones including patient tumor samples that can be grown in the mouse and can be shared across laboratories. Our studies have the potential to help with prevention, early detection, and treatment of head and neck cancers.

Matthew Galsky, M.D.

A standard treatment for bladder cancer that has invaded into the muscle layer of the bladder is to first give chemotherapy medication for several months and then surgically remove the bladder. Surgical removal of the bladder is a major operation and is associated with a potential risks. Also, because the bladder is where urine is stored in the body, when the bladder is surgically removed, the urine has to exit the body differently. For many patients, this means that the urine will be drained into a bag outside of the body called a urostomy. When chemotherapy medication is given through a vein for several months prior to surgery to remove the bladder, sometimes there is no more cancer in the bladder specimen when it is taken out of the body and inspected in the laboratory. If we could identify which patients might have their bladder cancer eliminated with chemotherapy medication alone, this could mean that some patients may be cured without having their bladder removed. We are testing whether given chemotherapy together with immunotherapy, medication to enhance the body’s immune system to fight cancer, is better at completely eliminating cancer in the bladder and also testing whether we can identify patients that are the best candidates for this approach by studying several features of an individual patient’s cancer before and after treatment. If our work is successful, we hope to be able to select patients who can have their bladder cancer cured with the combination of chemotherapy and immunotherapy without requiring surgical removal of their bladder.

Nir Hacohen, PhD

Funded by the Scott Hamilton CARES Foundation

Most cancer treatments — such as chemotherapy, radiation therapy and targeted therapy — work by direct killing of cancer cells. Some of the recent and most powerful therapies work by stimulating the patient’s own immune system to kill cancer cells. While these new immune-based therapies work better than most previous therapies and are now approved for treating 13 cancer types, they do not work for all patients. To understand why these treatments works for some patients and not others, we need better tools to investigate how the immune system interacts with cancer. We have developed a new way of growing tumors outside patients’ bodies to study how tumor cells and immune cells interact with each other. Our goal is to study how different types of immune cells stop cancer growth. We use our new method for growing tumors outside of the body to test out new treatments designed to steer the immune response towards tumor cells more effectively. If initial tests are successful, we will aim to try these new treatments in patients with melanoma and potentially other types of cancer.