Funded through the Stuart Scott Memorial Cancer Research Fund by the Marks Family in honor of Lisa Curtis
The human body is estimated to remove over a billion cells every day, a process achieved by a relatively rare population of cells called phagocytes. When a phagocyte ingests a dying cell, it essentially doubles its content (analogous to a neighbor moving into your house). Yet, phagocytes such as macrophages often ingest multiple targets in quick succession. How these phagocytes maintain their homeostasis and manage the excess influx of dead cell cargo, are interesting scientific problems that are largely unexplored. This is an important topic in understanding cancer development broadly, and the development of cancer therapies specifically, because the clearance of cancer cells directly establishes an environment for the tumor to grow. Exciting avenues of therapy involve trying to either break down this tumor-promoting environment or by increasing the immune response against the tumor. These approaches show much promise; however, they often only work in specific patient populations. We believe that to develop a more effective therapy, we must understand the underlying processes that link clearance of cancer cells to generating an anti-cancer immune response. To this end, my lab focuses on studying phagocytes that are prevalent in Triple-Negative Breast Cancer (TNBC), how tumor cell clearance contributes to TNBC progression, and discovering new ways to target these cells to treat TNBC.
Funded by the Constellation Gold Network Distributors
Non-Hodgkin Lymphomas are common cancers which can be cured in some patients by combinations of multiple chemotherapy drugs. Currently, these treatments consist of giving many drugs at the same time, waiting some weeks to recover from side effects, and repeating the cycle several times. We have discovered that in the most common combination therapy for Non-Hodgkin Lymphomas, while the use of many chemotherapies kills more cancer cells, the drugs do not enhance one another’s activity. Instead, certain drug pairs interfere with one another’s effects. This suggests that treatment might be more effective at killing cancer cells, and cure more patients, if this interference were avoided. This could be accomplished by giving certain chemotherapies at different times from each other. We will study a few lymphomas and measure how chemotherapies interact to determine which should or should not be given at the same time. A computer model will simulate how tumors respond to combinations of drugs given at various times. This simulation will use measured drug interactions to predict which treatment designs will be most effective at killing cancer cells. We will test these treatments on human lymphoma cells, and compare them to the current ‘all-drugs-at-once’ strategy. If this research finds a more effective approach to treatment, it can next be tested in animals, and eventually in human clinical trials. Ultimately we hope to identify a simple change in the use of already approved medicines that has the potential to cure more cases oflymphoma.
In the last three decades, no new drugs that can effectively treat pancreatic cancer have been found. One of the major problems in pancreatic cancer is that most research is performed on patients where the cancer has not spread to the rest of the body. This is because these patients are eligible for surgery and researchers have access to the tissue for experiments. However, most patients with pancreatic cancer are diagnosed when the disease has already spread. Patients where the disease has spread do very poorly compared to patients where the disease has not spread. We believe that there are changes in the cancer’s DNA that cause the disease to spread.
To investigate this, our laboratory compared the DNA from patients where the disease had or had not spread, and found that a gene that can potentially promote the spread of this cancer. This gene, named KRAS, multiplies inpatients where the cancer has spread. Patients where this gene has multiplied are very resistant drugs used to treat this cancer. The goal of our project is to understand how the multiplication of this gene is related to therapy resistance. Using specialized techniques in our laboratory, we will grow tumor cells from patients with and without multiple copies of KRAS to figure out changes in the cell that are related to this specific genetic change. We intend to use this information to find new drugs to treat patients where the cancer has already spread.
Funded by the Hirsch Family in memory of Ann Hirsch
There is a strong need for new treatments for brain tumor patients. To address this need, we asked how a common mutation in brain tumors may create weaknesses that we could use to develop new treatments. We identified a process that brain tumor cells with this common mutation rely on to live. Next, we used a drug to block this process and found that it kills brain tumor cells with this common mutation. We would like to know why these cells rely on this process and whether brain tumors grown in mice respond to this drug. If our work is successful, our efforts could lead to new studies that will test this drug in human brain tumor patients. We are hopeful that our discovery could lead to improvements in the lives of brain tumor patients.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Leukemia is the most common cancer among children in the US. It is also the leadingcause of death from cancer before 20 years of age. Despite advances in diagnosis and treatment, a subset of leukemias affecting infants predict poor outcomes. Leukemic cells in these patients carry a fusion gene known as MLL rearrangement (MLL-r). MLL-r is critical for the development of leukemia cells, and has been well studied over the years. However, current therapies targeting MLL-r showed modest clinical activity. Therefore, there is a need of finding additional drug targets. We have found a previously unknown protein complex required for the survival of MLL-r leukemic cells. In this project, we propose to test if blockingthis complexdelay the growth of MLL-r leukemia in cells and animals. We will also investigate the molecular mechanisms behind. Taken together, our work will provide preclinical evidencefor a new protein complex as a potential target for MLL-r leukemias. More broadly, our technologies will help the study of other childhood cancers.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Alveolar rhabdomyosarcoma (ARMS) is an aggressive cancer of the muscle that occurs in young children and teenagers. Despite years of attempts to improve chemotherapy regimens, survival of patients with ARMS remains poor. Thisisespecially true for patientswho have advanced disease at the time of diagnosis. ARMS tumors typically possess a single and defining genetic mutation.Abreak in one specific chromosome will fuse with another chromosome, creating a fusion gene. These fusion genescan control hundreds or even thousands of other genes and transform a normal cell into a cancer cell. My project focuses on the PAX3-FOXO1 fusion. This fusion causes the most severe form of ARMS. However,there are no therapies that target PAX3-FOXO1 directly. Our goal is to understand how PAX3-FOXO1 transforms a normal cell into a cancer cell so that we canfind new and precise therapies. To study this, we use zebrafish as a disease model because they are genetically similar to humans. We will integratethe human PAX3-FOXO1 fusion geneinto the zebrafish genome to determine the stepsrequired for ARMS tumor formation. For example, often normal development is hijacked by cancer genes. Our studies will determine if and how this happens in ARMS. Directly comparing zebrafish and human ARMSwill pinpoint the most important drivers of disease and likely find new options for more targeted and specific therapies.
Melanoma is an aggressive form of skin cancer that frequently spreads (metastasizes) to other organs. While some patients with metastatic melanoma benefit from novel drug therapies, such as immunotherapies, which reinvigorate the body’s own immune system to detect and eliminate cancer cells, most patients do not. Interestingly, patients who have metastasis to the liver are significantly less likely to respond to immunotherapies, and the underlying reasons are unclear. Here, we established a melanoma mouse model that, similar to patients, experiences liver metastasis, and therefore enabling us to study the impact of these lesions on responses to immunotherapies. We use cutting-edge methods, such as genome-editing tools and high-resolution molecular profiling and imaging methods to dissect both how liver metastases develop and how they impact the immune system in the entire body. The ultimate goal of this work is to develop improved therapies for melanoma patients with metastases to the liver.
Funded by the Constellation Gold Network Distributors
The human body generates hundreds of billions of new blood cells every day to replace old and dying cells. These new cells come from stems cells that live in the bone marrow. Sometimes the genetic material inside one of the stem cells is altered in a way that changes its behavior. The altered stem cells produce too many blood cells and slowly take over the bone marrow. In the clinic, we diagnose this as a type of blood cancer (called myeloproliferative neoplasm or MPN). Intriguingly, the same genetic alteration in different patients can result in very different forms of the disease. The disease outcome is just as unpredictable. Some patients show no symptoms for decades whereas others rapidly deteriorate. To understand this disease, for each patient, we would like to know where and when the disease originated and how the cancer cells expanded over decades. To answer these questions, we have developed technologies that allow us to measure molecular profiles of individual cells. To reconstruct the history of the disease, we will use the genomes of individual cancer cells in the same way that the evolutionary history of species is reconstructed from their present–day genomes. Our preliminary work has shown that cancer first occurs decades before diagnosis. Finally, to test therapies, we will engineer mice in which individual cells record their lineage histories in their own DNA. Together, our measurement will provide the most comprehensive molecular history of how cancers originate and progress in individual patients.
Funded by the Constellation Gold Network Distributors
Pancreatic cancer is one of the deadliest cancer types in the world. Most pancreatic cancer patients already developadvanced disease and are not suitable for surgery. A very small number of patients can live longer than ten years after surgery and are referred to as long-term survivors. Recently, unique bacteria were found in tumors from long-term survivors but not patients with shorter survival.In addition, long-term survivors tend to have higher numbers of T cells in their tumors – a cell type that is central to the immune system. Therefore, T cells might induce more powerful immune responses against cancer in long-term survivors through these unique bacteria.More precisely, we think that T cells in long-term survivors might “see” antigens from the bacteria and at the same time similar antigens from cancer cells. Our study is designed tounderstand the T cell responses unique to long-term survivors through T cell specificity inferences with our computer algorithms. The specificity inference will furtherguideour effortin finding these antigens that are “seen” by T cells in long-term survivors. Identifying these antigens from both cancer cells and the unique bacteria in long-term survivors will help usinventnew and better treatments for pancreatic cancer patients.
Cancer is a major cause of death worldwide. Immunotherapy is one of the most promising new ways to treat advanced stages of cancer. It works by “taking the breaks” off the immune system to let immune cells kill cancer cells better. Immunotherapy has revolutionized the treatment of cancers like melanoma, lung cancer and bladder cancer. Still, many patients do not respond to treatment. It is hard to know early who will respond and who won’t. We are developing and testing a method to predict response to immunotherapy early. We are doing this through a simple blood test thatmeasures signal from immune cells deep inside a patient’s tumor. We are testing our method in melanoma patients. If successful, our method will revolutionize the ability to predict cancer response to immunotherapy. This will give doctors vital information early and improve patient survival.
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