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.
The proposed studies will address two major issues in treating two hematological cancers, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): limited new and effective treatments for the last 30 years; treatments that are optimal on a patient-specific basis. MDS and AML cells arise in the bone marrow from healthy hematopoietic stem cells. Accumulation of several mutations is involved in this process. In addition, other cells in the bone marrow can affect MDS or AML development or progression: stroma cells that give rise to bone, fat and other cell types. We have identified a new pathway of communication between MDS or AML cells and stromal cells. At least 35% of MDS and AML patients express high levels of JAGGED1 in their bone cells. Our studies in mice show that JAGGED overexpression leads to MDS/AML development. Conversely, blocking JAGGED1 in mice treats MDS and AML and prevents lethality. We generated human antibodies that block JAGGED1 activity and can be used in treating MDS and AML patients. Our purpose is to test efficacy of the most active human antibodies in all subtypes of MDS and AML using mouse models and cells from patients. We have developed a robust and simple screening test for identifying the patients who have the JAGGED1 pathway active using cells from their bone marrow. Our studies will benefit patients by screening and identifying the ones with pathway activity that can be treated with the antibody. This patient-specific approach should increase the precision and efficacy of treatment.
Partially funded by the Stuart Scott Memorial Cancer Research Fund and the V Wine Celebration in honor of First Responders
Nick Valvano Translational Research Grant*
Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) originate from abnormal blood stem cells which have acquired multiple molecular aberrations over time and generate the bulk tumor cells that are diagnosed in patients in the clinic. Conventional therapies inhibit the bulk tumor cells; however, they do not eliminate the early blood stem cells that are the true root of the disease. Recent work has uncovered unexpected diversity of stem cells in patients with MDS, detected through a new methodology which we recently developed. Cancer/leukemia development is, at least in part, promoted by exposure to environmental toxins. The terrorist attacks on the World Trade Center created an unprecedented environmental exposure to aerosolized dust and gases that contained many carcinogens, and over the past few years we have built a large repository of samples from 9/11 first responder fire fighters, and non-exposed fire fighters as a control. We will leverage this unique sample repository and our newly developed methodology to study over time blood stem cells of individuals who have donate samples to this repository. Our study will be instrumental to improve diagnostic assessment, including at blood the stem cell level, and this may help to improve treatment selection focused on the true root of the disease. In addition, our study may be helpful for the development of treatment strategies for the prevention of leukemia in the future.
According to estimates from the International Agency for Research on Cancer, worldwide, there were 18.1 million new cancer cases diagnosed with 9.6 million deaths in 2018. In other words, one in 5 men and one in 6 women experience cancer during their lifetime, and one in 8 men and one in 11 women die from the disease. As such, there is an urgent need for finding better treatments to reduce cancer-associated death. BRCA1 and BRCA2 are two genes that, when mutated, can cause cancer. Studies by many research groups have revealed critical roles of BRCA1 and BRCA2 in protecting our genetic material from damage caused by sunlight, radiation, and other environmental exposures. While BRCA mutations have been linked to a greatly increased risk of developing cancer, we do not yet fully understand the biological process of DNA repair mediated by the BRCA genes. This poses a challenge for patient counseling, determining prevention strategies, and the formulation of treatment plans when disease strikes. Here, we describe a research project to study BRCA1 and BRCA2 designed to fill this knowledge gap. The information and tools from our work will help explain why BRCA mutations cause disease and help formulate treatment regimens that are more effective than current ones.
Head and neck tumors are composed of cells that are not all the same, but instead have different functions, much like bees in a hive. While some cells act like drone bees that are primarily responsible for expanding and growing the colony (or in this case, tumor), others are responsible for directing and orchestrating the tumor like a queen bee. Still other cells mimic worker bees who travel outside the hive and are responsible for the spreading the tumor to new locations. We are interested in these worker bees of head and neck cancers and understanding what triggers them to exit the hive. In particular, we are trying to identify the specific genes that serve as markers of the worker bees, in order to determine if they are present in tumors and whether they can help to predict when a cancer may spread. We are also trying to understand the specific genes that allow these worker bees to perform their function. Much like a specific wing shape or other adaptations worker bees have in nature, we are curious about whether these cells have specific cellular machinery they use to spread beyond the tumor. Together, these studies could help us develop new ways of identifying patients at risk for their cancer spreading as well as new treatments to prevent the spread of cancer all together.
Mailing List
