The most common mutation found in patients with pancreatic cancer is a mutation in the Kras gene. However, this mutation is not sufficient for initiation and progression of pancreatic cancer. It is well known that inflammation is a risk factor for pancreatic cancer and can accelerate pancreatic cancer development. We have shown that during pancreatic inflammation, caused by cigarette smoking, stones, or other stressors, immune cells secreting a factor named IL-17 are recruited to the pancreas and are capable of inducing pancreatic cancer initiation and development. We are now interested in understanding the role of these cells in regulating pancreatic cancer stem cells induction and invasiveness. This information will be useful for pancreatic cancer prevention and treatment given the existence of commercially available monoclonal antibodies that target specifically these cells.
Funded by the Stuart Scott Memorial Cancer Research Fund
Multiple myeloma is an incurable cancer of plasma cells. There is no cure for multiple myeloma yet. The T cells of the immune system can protect us in the long term from infections and from cancer. Here, we propose to engineer human T cells so they can recognize and kill myeloma tumor cells. This project will test several ways of engineering the T cells to make them as safe as possible and as effective as possible. Our goal is to use this information to treat human patients with multiple myeloma.
Funded by the Dick Vitale Gala in Memory of John Saunders
Our goal is to understand why infants get a type of cancer called leukemia. Infant leukemia is devastating, and most of these children will die of their cancer. A common question parents ask is, “Why did my child get this disease?” Our work suggests that the cause is, at least partly, genetic. My lab is developing tools to determine which genetic changes are actually important for causing infant leukemia and which are not. We are focusing on changes that are inherited from generation to generation, even in families that have no history of infant leukemia. Through our studies, we hope to answer the “Why?” question for parents and other relatives, and we hope develop new treatments for infant leukemia that are more effective and less toxic.
Pancreatic cancer is a very aggressive disease. The 5-year survival rate is a shockingly low 8%. This statistic has hardly changed in 30 years. This is because effective treatment options for pancreatic cancer do not exist.
A notable feature of pancreatic tumors is a scar-like barrier that protects the cells from anti-cancer drugs. This barrier also restricts oxygen and nutrient access, placing the cancer cells on the brink of starvation. The Lyssiotis lab seeks to figure out how these cancer cells survive and grow with limited nutrient access.
Pancreatic tumors are also known to be made up primarily of non-cancer support cells. My lab recently found that these non-cancer cells provide the cancer cells with nutrients. In this proposal, my laboratory will determine the role of these nutrients on tumor growth. A means to block this pathway would starve the already nutrient deprived cancer cells. This will provide important insights to design new therapies for this dreadful disease.
More than 40,000 American women die of breast cancer each year. One out of every eight women in the U.S. will develop invasive breast cancer during their lifetime. In 70% of these women, estrogen and estrogen receptor α (ERα) are key players in breast cancer diseases. Keeping this endocrine signaling function low by endocrine therapy is the best treatment right now. Yet, after 5 years, hormonal treatment stops working in more than 30% of these patients and the disease returns. Because hormone resistance is still a challenge, there are few effective therapies for these patients. We plan to study estrogen and ERα related to hormone resistance.
ERα binds DNA elements that regulate gene expression. These elements are very important in cancer development and progression. When these elements lose control, breast cancer becomes resistant to hormones. Thus, if we can find ways to understand and correct these elements in hormone resistant cells, we can find cures for ERα-positive breast cancers. The goal of this project is to understand how ERα controls DNA elements. We will identify markers to measure the presence and progression of breast cancer. Our research results may lead to new therapies that target this disease. Discoveries from this project may help with treating other cancers and may be useful for other research fields.
Despite great progress in treating cancer in children, we are still not able to cure all patients, especially those who relapse or do not respond to standard therapy. In T-cell acute lymphoblastic leukemia (T-ALL), children and adults have poor outcomes because of resistance to existing therapies. Therefore, there is an urgent need to identify new treatment strategies. The term “epigenetics” refers to the environment in the nucleus that is surrounding the DNA in cells and can determine which genes are turned “on” or “off.” The recent discovery that epigenetic changes can contribute to cancer development is key because they may be reversible and targeted with novel anti-cancer drug therapies. Although many tumors have epigenetic alterations, their relevance is not well understood. My research aims to understand epigenetic changes and their consequences in cancer. The research funded by the V Foundation will investigate what causes the epigenetic changes in drug resistant T-ALL. This research holds great promise for revealing new information about the biology of T-ALL and has great potential to bring effective new therapies to patients with this type of blood cancer.
Breast cancer is divided into different categories, called “subtypes”. These subtypes are based on proteins that are present or missing in a patient’s tumor cells that signal them to grow in response to hormones or other factors. This is important because the cancer therapy most likely to be successful is chosen based on the patient’s cancer subtype. Although some subtypes respond to certain drugs, approximately 10 – 20% fall into the “triple-negative” breast cancer (TNBC) subtype, which is one of the most aggressive types of breast cancer. It is difficult to treat and often comes back, even when the initial therapy appears to be effective. This is why we urgently need new ways to treat TNBC. Research findings show that certain signaling proteins, kinases and phosphatases, are often changed in TNBCs. They control cell growth, response to drugs, and cell death. Drugs that target kinases have shown great success in cancer therapy. However, tumors often adapt to them, and these therapies stop working. Using combinations of drugs can overcome this, but it is hard to predict which drugs will work best together. Although kinases have been studied in great detail, less is known about phosphatases and their function as tumors adapt to therapy might help us to better treat TNBC. We have developed a new approach to study phosphatases in tumors and cancer cells. Our analyses will help to determine their role in TNBC, identify new targets for drug development, and improve predictions for combination drug therapies.
Funded by the 2016 Vitale Gala in memory of Julia Mounts.
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Treatment and survival for children with RMS has not changed for thirty years. Aggressive treatments result in deformities and other health issues in survivors. This highlights a need for more understanding of RMS. Identifying the key features of RMS would guide the search of new treatments. The Pediatric Cancer Genome Project (PCGP) at St. Jude Children’s Research Hospital identified many genetic changes in RMS. The most common subtype of RMS is embryonal rhabdomyosarcoma (ERMS). ERMS had many different genetic changes.
It remains unclear which identified genetic changes drive ERMS formation. Identifying the drivers will expose new targets for treatment. Our lab proposes to identify the essential drivers of ERMS. We will utilize a cell-based approach to explore the genetic changes identified by the PCGP. This system allows us to quickly test the effect of each of the potential driving changes.
We will develop new model systems that more closely resemble our patient’s tumors. Next, we will use these simple models to test new treatments. It is our hope that models with the minimal gene changes necessary for ERMS will simplify our search for new treatments. The result will enable us to pinpoint methods to kill tumor cells. The long-term goal is to couple the specific genetic changes to new therapies.
Ovarian cancers are among the most deadly cancers for women. We need better drugs to treat women with ovarian cancer. Recent studies show that certain ovarian cancers have mutations in unique genes. For example, 60% of epithelial ovarian cancers (EOC) have mutations in the ARID1A gene. This is an important clue to understand EOC and how to treat it. ARID1A mutation forces these cancers to rely on the related protein ARID1B. ARID1B is thus an attractive target for drug discovery. ARID1A and ARID1B are proteins that control gene transcription. However, we do not why ARID1B is vital for ovarian cancers. Using new methods, we will find the genes that ARID1B controls in EOC. We will design a system to eliminate ARID1B in EOC to test if ARID1B is a good drug target. Cancers can often find ways to escape our drugs and come back. We will find loopholes that ovarian cancers use to escape ARID1B elimination. Our goal is to find new strategies to treat women with ARID1A mutant EOC.
Funded by the Stuart Scott Memorial Cancer Research Fund
The human gut contains trillions of bacteria. In fact, there are more bacteria in the gut than there are cells of the human body. To protect the body from gut bacteria, immune cells constantly battle with gut bacteria. This battle occurs inside every person but in some, this battle can cause tumors to grow. Tumors often grow in the colon and this type of cancer, called colorectal cancer, is the location where most gut bacteria dwell. How can the battle with gut bacteria cause colon tumors to grow? To answer this question we must first find out which immune cells control and design the battle plan. We think that the battle plan against gut bacteria is designed by a special immune cell, the dendritic cell. There are many different types of dendritic cells and we found that each has a different battle plan. We want to find out which dendritic cells enter colon tumors, which dendritic cell’s battle plan cause tumors to grow, and which battle plan may help fight the tumor. When colon tumors grow we think that gut bacteria force the dendritic cell to make proteins that shield the tumor from attack and help the tumor to grow. We are testing these ideas by changing how dendritic cells respond to gut bacteria, to find out how this changes the battle plan, and to discover how this impacts colon cancer.
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