Blood cancer affects thousands of individuals each year, and despite impressive early therapeutic advances, cure rates for most blood cancers have reached a plateau. Moreover, most therapies that are currently used do not specifically target blood cancer cells and therefore lead to undesirable side effects in a large number of patients. There is therefore an urgent need for developing safer new drugs for this devastating disease. The focus of this research proposal is to define the molecular mechanisms of a specific sub-type of acute myeloid leukemia that mostly affects children and young adults but is also seen in older patients. In this project, we will make use of molecular, genetic and biochemical methods to identify ways and means by which genes that are mis-regulated in these tumors lead to cancer development. Based on our preliminary findings, we propose that our approach may lead not only to a more detailed understanding of this specific sub-type of blood cancer, but also to novel treatment strategies.
Funded by the Stuart Scott Memorial Cancer Research Fund
Cancer rates are falling in North America, with a few important exceptions. Liver and endometrial cancers in African Americans and Hispanics continue to rise. We try to decrease that disparity by identifying new characteristics of those cancers. Those characteristics allow doctors to determine if a patient will respond to new therapies. The characteristics also provide an incentive for drug companies to pursue new therapies, since the clinical trials are more likely to succeed.
But how do we find these characteristics? Why have they not already been discovered? The answer is that our lab made a new discovery about how these cancers grow. We found that a protein controls organ growth by placing a “molecular barcode” on the DNA. Under healthy conditions, this barcode is only present when an organ is supposed to grow. But in cancer the barcode is always present, commanding it to grow into a tumor.
The work we will do here tests if we can examine mouse liver tumors for these barcodes. The barcodes will allow us to develop new therapies for liver cancer patients. Those new therapies should stop tumor growth. The barcodes also provide a way for doctors to know which drugs will work for a particular patient. By personalizing medicine, we hope to make new and better therapies that are not worse than the disease.
New drugs that use the body’s own immune system to treat cancer have been one of the most exciting recent developments in cancer research. Studying the cancer cells in a tumor tells doctors a lot about how to treat that kind of cancer, no matter whether it appears in the breast, the brain or somewhere else in the body. Most types of cancer that respond to these new drugs have something in common: they tend to have high numbers of gene mutations, or DNA changes. Mutations sometimes cause changes that make the tumor cell look like it has been infected by a virus or bacteria. This makes the immune system attack the tumor, just as it would attack a cold or an infected cut on the finger. Most mutations have no impact on how aggressive a patient’s cancer is, so having more mutations is not a bad thing. In fact, patients whose tumors have more mutations often have better outcomes, probably because they trigger the immune system to start attacking the cancer. Unfortunately, many other cancer types have fewer mutations, and so may not respond as well to new drugs that stimulate the immune system. We suspect that a specific group of drugs may make some of these tumors respond better. In this study, we will try to find out if this is true. If so, it may be possible to begin testing the drugs on patients right away to help patients whose cancer does not respond to standard treatments.
Following surgery and treatment, breast cancer patients live with a high risk of developing a relapse. When tumors do recur, especially at distant sites, they are often incurable. Therefore, it is important to develop new approaches for preventing breast cancer relapse. The period between treatment of the primary tumor and the formation of a recurrent tumor is called dormancy. During this stage there are cancer cells somewhere in the patient’s body that are dormant, or not actively growing. These dormant cells are the source from which recurrences must arise. Understanding how these cells survive for long periods and designing ways to kill them is important for preventing recurrences.
Dormant tumors cannot be detected by current imaging methods, and so studying these cells in patients is difficult. We have developed mouse models that allow us to study dormancy and recurrence. Using these models, we have found that dormant tumors have a unique type of metabolism. In order to translate this finding to a potential therapy it is important to know more about this metabolism works, and whether dormant cells can be killed by targeting this metabolism. In this proposal we will use the mouse models we developed to address these questions. Once we understand more about dormant cell metabolism, we may be able to design drugs that can kill dormant cells and prevent breast cancer relapse.
Acute myeloid leukemia (AML) is a deadly blood cancer. Three of four patients with AML die within five years. Those who survive suffer harsh side effects from treatment. This problem has not changed in 30 years. We need to create new treatments that can cure AML before the disease becomes too hard to control. To do this, we need to learn what causes AML cells to grow in the body.
We now know that cancers grow not only because of changes in the cancer cells themselves, but also because of signals released by nearby healthy cells. Our lab found that an inflammation-causing protein called IL-1B plays a key role in AML by: 1) encouraging growth of AML cells, 2) stopping growth of normal cells around a tumor, and 3) preventing the body’s immune system from killing AML cells when cancer cells are growing. We will explore how to stop AML’s growth by blocking the communication between AML cells and this IL-1B signal. Blocking this signal could also allow the body’s natural defenses to recognize and kill AML cells. Our goal is to find new drugs to improve treatment and quality of life for AML patients.
Gliomas are aggressive brain tumors. Gliomas are very heterogeneous, which is a big problem for treatment. Traditionally, researchers have profiled pieces of tumor with a lot of cells all mixed together, thus masking many information differences. To precisely define brain tumors, I propose to use single cell sequencing techniques directly in patient samples. My laboratory is a leader in these techniques and has shown the potential of these approaches in cancer. I thus propose to: (aim1) perform single cell analyses in brain tumors in adults and children. I also propose (aim2) to use our new data to identify novel ways to target specific programs in brain tumors. Our research will provide the community with a very detailed view of gliomas and suggest ways to improve the treatment of patients.
Acute lymphoblastic leukemia is one of the most common and deadly childhood cancers. Drugs that children are given often do not fully kill all of the leukemia cells. A specialized cell, called a leukemia stem cell, preserves the leukemia through selfrenewal. If one leukemia stem cell persists, the cancer can regrow and make a child sick. Our goal is to find better ways to kill these cells so that we can cure patients. One way that we do this is by studying leukemia stem cells in a zebrafish cancer model, which is very similar to human disease. Here, we will use a new method to find genes that are only expressed by leukemia stem cells. We will then look for drugs that target these genes and can kill leukemia stem cells. The breakthroughs that we make can be quickly applied to human disease because our studies are being done in an animal model. Our research will give vital data about leukemia stem cells and biology, and we hope we will discover new drugs to treat leukemia.
Support for the Liposarcoma Genome Project was funded by
Alex Gould and Friends in memory of Kathryn Gould.
Liposarcoma Genome Project – Liposarcoma is the most common type of cancer that arises in soft tissue. These tumors often present as low grade tumors initially, but a subset of patients will experience recurrence of a higher grade tumor. Those patients who recur with higher grade tumors do poorly. Therefore, our research focuses on understanding these high grade tumors. We will explore the genetic changes between the low grade and high grade tumors in order to understand the molecular features that underlie high grade transformation. We will begin by sequencing gene mutations in these tumors and surveying gene activity in each tumor type (Aim 1). Mechanisms that govern which genes are on and off frequently involve how the DNA is packaged and structurally arranged in the cell. Therefore, we will characterize the packaging (chromatin) and structure (topology) of the genomic DNA in these tumors (Aim 2). By elucidating mechanisms by which tumor cells alter gene expression, we will better understand the genes and pathways that sustain them. Finally, we will develop models of these tumors (Aim 3). We can use these models to test driver genes and candidate therapeutic targets identified in our study. We believe that our interdisciplinary team of clinicians and scientists is poised to complete the proposed aims, which should yield important insights into liposarcoma biology and guide future clinical strategies.
