The spread of cells from one organ to another organ is the main cause of death for cancer patients. When cancer cells continue to grow and form a tumor some of them run out of oxygen. Cancer cells learn to deal with these low levels of oxygen by switching on genes that help them survive even under stress. As a result, rather than dying these oxygen-deprived cells become even more powerful and can continue to survive even when treated with cancer drugs. To investigate how these cells function we must find these powerful cells within a tumor. To do this we designed a trick to make the cells change color when they do not have enough oxygen. We can use this color to find and collect the cells from within a tumor. Once we collect the cells, we will try to determine what makes them so powerful and use this information to try to design methods to kill these deadly cells.
Funded by Hooters of America, LLC., in memory of Kelly Jo Dowd
Each breast tumor contains a unique set of genetic mutations that contribute to tumor growth and response to treatment. This means that each patient will respond differently to specific anti-cancer drugs. Triple negative breast cancers are an aggressive and deadly form of breast cancer. Treatments used for this disease often do not work and may have harmful side-effects. As such, there is a need to understand what causes these tumors. This knowledge will allow new therapies to be developed to improve breast cancer treatment. One such opportunity involves what is known as the PI3K/Akt pathway inside cells. This pathway is present in triple negative breast cancer and carries messages within the cell to drive various cell functions including cell growth and survival. When the PI3K/Akt pathway is active in other forms of cancer, it often responds to targeted drugs but not in triple negative breast cancer. These drugs may not work because few mutations are present in genes that are known to regulate this pathway. The goal of our research is to understand what regulates PI3K/Akt messaging in triple negative breast cancer. We propose to identify essential genetic alterations and determine how these genes might impact PI3K/Akt messaging and breast cancer. The proposed studies will result in a better understanding of PI3K/Akt signaling and serve as the foundation for personalized breast cancer treatment.
Funded by Hooters of America, LLC., in memory of Kelly Jo Dowd
In humans, an early age of first pregnancy reduces the risk of breast cancer by an incredible 30%. The effects or pregnancy on reducing breast cancer risk is present in multiple mammalian species, and confers a long-lasting cancer protection. However, we know little about the modifications that confers breast cells with a cancer resistant state. The goal of our proposal is to understand pregnancy-induced breast cancer protection and to discovery how to manipulate its effects. Our ultimate goal is to devise preventive strategies to mimic the preventive effects of pregnancy and potentially reduces breast cancer occurrence.
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.
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