Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Funded by the Stuart Scott Memorial Cancer Research Fund
PSA is a blood test used to check men for harmful prostate cancer (PCa). A man with high levels of PSA may have harmful PCa, but if we catch it early, it is almost 100% curable. Men with high PSA may also have harmless PCa or they may not have cancer at all. To diagnose harmful PCa, doctors take biopsies of the prostate using painful needles. Fortunately, most of the men end up having large prostates or harmless forms of PCa. This causes many men to suffer through the biopsy and then worry about potentially having a harmful cancer. Some men with harmless PCa will have surgery or radiation from fear, but can have bad side effects.
Prostate Health Index (PHI) is an improved version of PSA that better predicts which men have harmful, PCa. Doctors use PHI to help men avoid prostate biopsies. Unfortunately, PHI was never tested for accuracy in African American men (AAM). AAM have the highest chance of dying from harmful PCa. We need to prove that the test works in AAM like it does in White men. We will compare how well the test works for predicting harmful PCa in 300 African American men in comparison to 100 White men that are having a prostate biopsy. If PHI works, we will be able to detect harmful PCa earlier for African American men. This test will reduce their chances of dying from the disease.
In this project, we aim to develop a safe and effective treatment for a childhood cancer called neuroblastoma. Recently, there has been some success harnessing the human immune system to fight cancer. We have developed an immune-based strategy to target one specific cancer-promoting gene that is known to cause an aggressive form of neuroblastoma. This gene is present in about half of all cases with poor disease outcomes in our patient population. We developed a new cancer vaccine for this gene that causes immune cells in the body to fight cancer cells directly. A mouse version of this vaccine proved safe and potent in mice, so we think we can use the same strategy to create a clinical-grade vaccine that will be safe and effective in humans, too. In this study, we first will test each part of this vaccine separately and then will re-assemble them in a very clean laboratory room. Indeed, this vaccine will be produced under such strict conditions that it will be ready for clinical testing in children with neuroblastoma after this grant is completed. Because we are targeting a gene that is expressed on cancer cells but not on cells of healthy tissues, our vaccine is unlikely to be as toxic as others treatments that are available now in the clinic. This vaccine is easy to deliver, as it can be swallowed and so does not involve a shot, making it easier for pediatric patients.
Rhabdomyosarcoma is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood and adolescence. While most children with the embryonal variant of rhabdomyosarcoma are cured, there is a sub-group of children with high-risk features, making their chance of survival less than one in three. One hypothesis underlying these high-risk features is that there are rhabdomyosarcoma stem cells that can persist in the body despite current standard therapy. A goal of our research laboratory is to identify the cellular pathways that contribute to this persistence of rhabdomyosarcoma stem cells. Over the past several years we have observed that some cellular pathways active during normal skeletal muscle development have been hijacked by embryonal rhabdomyosarcoma cells. We even think that these development pathways communicate with one another to support and reinforce rhabdomyosarcoma stem cells. Our aim in this project is to understand how these cellular pathways communicate with one another, whether they can be inhibited by gene manipulations or pharmacologic agents, then test combinations of these treatments in rhabdomyosarcoma cells in culture and in laboratory mice. We hope to someday translate these findings to clinical trials, opening the door to new treatments for children with this disease.
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.
