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.
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.
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.
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.
Stomach cancer, the third-leading cause of cancer death world-wide, is classically divided into two primary types, one of which is called Diffuse Stomach Cancer (DSC). DSC is a very aggressive and rapidly-lethal disease where we lack effective therapies. Additionally, DSC also impacts a relatively unique group of patients. DSC is increasingly common in young females, often women in their 30’s-40’s and is also highly prevalent in the Latin American and Native American populations. Unfortunately, although DSC patients are in tremendous need of therapies, there has been relatively little laboratory research seeking to understand biology of these cancers or to develop new, more effective therapies. At our cancer center, we have established a new collaborative research programaiming to address this critical unmet medical need. We have built off of the progress we have made by studying the specific genes that are abnormally turned on in these cancers. Over the past years we have specifically studied the biology of DSC and have defined new highly promising candidate therapeutic approaches. Additionally, our collaborative team has developed new cancer models (cancer cells we can grow and study in the laboratory) from Latin American patients’ (and young females’) cancers. We now propose to bring together our new candidate therapies and this new collection of patient models to prepare optimal therapeutic approaches for DSC into clinical trials. This work will enable us to rapidly bring the most promising new therapeutic approaches into patients, including under-represented minorities whose cancers are often not adequately studied.
Pancreatic cancer is the 3rd leading cause of cancer-related death in the United States, with a five-year survival rate of less than 9 percent. Activation of the immune response in the microenvironment is associated with better outcomes in pancreatic cancer patients. The tumor and gut microbiota has recently been shown to influence tumor progression by modulating the tumor microenvironment.
We have recently demonstrated that the composition of the gut microbiome may determine tumor behavior and outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. We have identified specific bacteria signatures in the tumors of long-term survivors (LTS) compared to the stage-matched- short-term survivors (STS). We have also shown that transplantation of fecal microbiome from LTS or healthy controls of pancreatic cancer patients into a mouse model of PDAC significantly reduces pancreatic cancer growth. These important findings prompted us to target tumor microbiome as a therapeutic approach in pancreatic cancer patients. Here, we propose to transplant stools from PDAC long term survivals or healthy controls into PDAC patient to change their immune suppressive behavior to immunoactivated one. To this end, we will first analyze the changes in microbiome of PDAC patients after the transplantation of gut microbiome from long term survivals or health controls. Next, we will evaluate the tissue obtained from biopsy and surgical specimen for the changes in tumor microbiome of PDAC patients. Finally, we will characterize the tumor immune infiltrates from tissues obtained from PDAC patients to see if we can switch PDAC immunosuppressive TME into immunoactivated by fecal microbial transplantation. This proposal would be the stepping stone to move forward efficacy trials in PDAC patients combining FMT with standard treatment or immunotherapy.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. CLL starts in the bone marrow in a type of white blood cells called B-lymphocytes. Standard chemotherapy has been successful in treating most patients, but drugs often are not effective when a small group of leukemia cells have specific changes in their DNA. In our earlier work, we used advanced DNA sequencing and found mutations that were present in only a few leukemia cells. These mutations, which were not found by common approaches in the clinic, changed the function of a gene called TP53. The cells that had these mutations became the major leukemia population when CLL came back. To treat such high-risk patients, new drugs have been developed, which disrupt the processes that leukemia cells use to interact with their environment. Similar to resistance against chemotherapy, some cells, which may have alterations that stop the drug from working, are not killed and can result in CLL’s return. In this project, Rutgers Cancer Institute of New Jersey and the Institute of Oncology Research will work together to analyze patient samples collected during treatment in a clinical trial, and apply highly sensitive experimental approaches to thousands of single leukemia cells to develop models that help us understand how CLL cells behave and change under new therapies. We will test our results in independent groups of patients who are being treated with the same drug, with the goal of finding new ways for doctors to diagnose and treat patients.
