Our goal is to develop a potent therapy for pancreas cancer – an incurable disease that is resistant to traditional cancer treatments. Challenges involved in treating this disease include: i) a barrier that surrounds the cancer cells (“tumor stroma”) and limits drug access, ii) diversity among cancer cells, making it hard to find a single means of killing all cells, and iii) the harsh cancer milieu, which prevents immune cells from working. Thus, new therapies to beat these barriers are vital and T cell therapy may meet this need. We plan to collect immune cells, called T cells, from patients and in the laboratory we will train them to find and kill tumor cells that display “tumor associated antigens – TAAs” on their surface. We plan to use cells that have been trained to look for tumor cells expressing 5 different TAAs in a clinical trial where we will gauge if this therapy is both safe and active in patients. Next, to ensure that our cells retain their ability to kill in the tumor milieu we will equip them with a special switch that allows them to convert bad signals into ones that are good for our T cells. Hence, we will turn an “off” switch into an “on”. By using this tactic, we hope to boost the activity of our therapy.
Diffuse large B-cell lymphoma (DLBCL) is the most common blood cancer. Most patients with DLBCL are cured with treatment. People are more likely to die if they do not get standard treatment or if they have a worse type of DLBCL. DLBCL can be divided into two major types: GCB disease and ABC disease. 90% of GCB patients and 44% of ABC patients are alive 3 years after standard treatment. We think that the same number of ABC and GCB DLBCLs occur. We do not know if there are racial differences. We saw that African-American patients get DLBCL at a younger age than white patients and more often die. We also saw that in the past black patients did not get standard treatment as often. We want to understand why African-Americans have worse survival. We will examine differences in the numbers of ABC DLBCLs in the population of the state of Georgia. We will collect DNA to examine the genes linked to ABC DLBCL. This will be the first statewide study to collect data on the genetics of DLBCL, the treatment that patients received, and their survival. From this, we plan to identify which factors are most important to target to eliminate racial disparities in cancer survival.
This project is focused on small cell lung cancer (SCLC). There are about thirty thousand patients diagnosed with SCLC in the United States each year. Unfortunately, this disease is rapidly fatal in most cases. We are taking new approaches to better understand SCLC and to develop improved treatments for this disease. First, we are developing new models to study this disease in the lab. These models use tumor material from patients that we grow in mice. Second, we then study the behavior of these tumors in these mouse models. We will study why tumors respond or don’t respond to certain therapies. We will specifically focus on studying a new therapy that we are using to treat patients in an ongoing clinical trial. Third, we will use these models to develop new treatments for patients with SCLC. Ultimately, our goal is to develop improved therapies and outcomes for patients with SCLC.
Acute myeloid leukemia (AML) is one of the deadliest blood cancers. Current treatments are very toxic and most patients will die from their disease. Metabolism is the process that converts food into energy and building blocks for making and maintaining our tissues. Metabolism is also essential for cancer cells and we have known for over a hundred years that cancer cells have different metabolism requirements than normal cells. The challenge has been to fully understand these differences and to target these unique requirements to kill cancer cells without killing normal cells. The DeGregori lab has generated exciting data showing that a new therapy for AML (“FLT3-inhibitor”) results in dramatic changes in metabolism within leukemia cells. FLT3 has been shown to be important for the formation and growth of AML. The new FLT3-inhibitor therapy is being tested in hospitals for patients with AML. However, while a lot of AML cells die after treatment with FLT3-inhibitor, enough leukemia cells survive to rapidly cause the AML to come back. Proposed studies will attempt to take advantage of the new weaknesses of AML cells caused by this therapy, in order to develop new combination therapies that better eliminate leukemia cells with reduced side-effects to the patients. These new therapies will be like “one-two punches”, with the first punch (FLT3-inhibitor) weakening the AML cells. The second punch takes advantage of this weakness, helping to eliminate the surviving AML cells. The development of these new combination treatments is expected to lead to better results for patients with AML, using less toxic drugs.
Each year in the United States over 30,000 patients with breast cancer are treated with a class of drugs known as the anthracyclines. The anthracyclines are one of the oldest and most effective chemotherapies for breast and other cancers. However, some patients do not benefit from this therapy for reasons that are not understood. Moreover, because the anthracyclines target TopoII isomerase (TopoII), a remarkable protein that is vital for normal cellular functions such as untangling DNA, they can have serious side effects. Recently, we have found that we can predict whether cancer cells will respond to TopoII inhibitors based on their genomic profile. Our over-arching goal is to spare patients treatment with this highly toxic class of drugs if they will not benefit from their use. By performing a simple genomic test on the patient’s tumor sample obtained at the time of diagnosis, we aim to predict which patients will benefit from anthracyclines and thereby inform treatment decision-making. In this manner, treatments can be personalized so that patients receive the best possible current therapy to treat their specific tumor, while being spared ineffective drugs and their side-effects.
Triple negative breast cancer often strikes young African-American and Hispanic women and spreads to the lungs and brain. There are no approved drug treatments for this type of breast cancer other than chemotherapy. Clearly, there is a pressing need to develop better treatments for this disease. We have developed a new approach that uses diet to prime tumor cells to respond better to cancer drugs. The diet we are using is similar to a vegetarian diet. We will test this diet in combination with a new drug that kills tumor cells in mice and in patients with triple-negative breast cancer. We predict that the combination will be better than the drug alone. Our goal is to improve survival for patients with triple negative breast cancer.
Despite improvements in treatment, breast cancers recur in some patients years after their initial treatment. Recurrent cancers arise from the small number of cancer cells that survive standard treatments, and ultimately resume growth. We have developed a way to find these cancer cells in mice and in patients, have identified how these cancer cells survive, and have found drugs that can kill them. In particular, we have found that treating mice with drugs that block a protein called “c-MET” can kill residual cancer cells and thereby prevent breast cancers from recurring. Our goal is to now to determine whether we can use this approach in patients. To accomplish this, we will first study when c-MET gets “turned on” in cancer cells that survive treatment in patients. Second, we will treat mice bearing cancer cells with the anti-c-MET drug to determine if it will kill these cells and thereby prevent breast cancers from coming back. Third, based on these findings we will plan a clinical trial for women with breast cancer that will be able to determine whether anti-c-MET drugs can kill residual cancer cells and, ultimately, whether it can reduce recurrence and increase the likelihood of cure.
Leukemia is a type of blood cancer. Leukemia is the most common cancer in children. Overall, the chance that a child with leukemia can be cured is high. However, when leukemia occurs in babies, the chance of cure is much lower. We are trying to find new and better treatments for these babies. These leukemias have abnormal ways of organizing their DNA. This may be making them harder to cure. We want to understand this better. We want to find new treatments that can fix this abnormal DNA organization. We hope this will help cure more babies.
Uterine cancer is a cancer that grows in the lining of a woman’s uterus (womb). In the United States, uterine cancer is the most common cancer of the female sex organs. Most often, women with this type of cancer have periods that are not normal or have bleeding after they have gone through menopause. By the time this bleeding starts, the cancer may have spread to other sites and organs. If it is caught at an early stage, it can be treated more easily and there is a higher chance of cancer cure. Right now there is not a screening test for this cancer. Our research project aims to design a simple screening test for uterine cancer.
Uterine cancer is caused by changes in the normal cells lining it. These changes can be found in the blood and fluid that passes into the vagina from the uterus. This fluid can be collected using a tampon. Better understanding changes in normal sex organ tissues and in different types of uterine cancer will help us identify the changes that truly represent the presence of a cancer. Our screening test will find the changes that identify cancer in fluid that can be collected using a tampon. We also expect that the cancer changes will be found even in women without bleeding that have an early cancer. The hope is that finding cancer early will lead to improved cancer outcomes.
This research will help us improve a new type of therapy for children with neuroblastoma. Neuroblastoma is a deadly tumor in the nervous system outside the brain. With this therapy doctors administer both chemotherapy and a protein (antibody) that attaches to tumor cells at the same time. This combination, a form of chemo-immunotherapy, was tested on children whose tumors had not decreased even after many rounds of chemotherapy. These children would have died, but chemo-immunotherapy literally melted the tumors off after a few rounds of treatment. The results of this study have not been published yet but are already being used by doctors to successfully treat these children.
Despite this great outcome, half of the children did not respond to the new treatment. There is still a lot to learn about chemo-immunotherapy. In this study, we will test patients’ tumors and find out how their blood cells change with chemo-immunotherapy. We hypothesize that chemo-immunotherapy is assisted by white blood cells destroying tumor cells. Our goal is to study how tumor cells stop or slow down the effect of this therapy. If we are successful, we can modify chemo-immunotherapy to work in all children with neuroblastoma.
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