Many cancers are treated with radiation therapy. Some cancers types are especially hard to treat. One type of cancer that affects the lungs and throat is only cured in about half of cases. Even when drug treatments are added to the radiation therapy, cure rates are not much improved. Also, adding drugs to radiation therapy can make the treatment hard for patients to tolerate. New treatment approaches are needed for these patients.
One new approach that is showing promising results is to give refined treatments that are more precisely targeted to each patient’s cancer. This approach is called Precision Medicine. Precision Medicine has not been used much for the cancer type that affects the lungs and throat. Also, Precision Medicine has not yet been used for radiation therapy. Instead, the standard treatment for these patients continues to be a one-size-fits-all approach.
We expect that the standard one-size-fits-all treatment approach could be replaced by Precision Medicine. The objective of our research is to develop new Precision Medicine approaches for the cancer type that affects the lungs and throat for use with radiation therapy. These new treatments could someday lead to higher cure rates and tolerability of treatment. If successful, our research will lead to new clinical trials that will test these new treatment approaches in cancer patients.
Breast cancer is the most common type of cancer in women worldwide. Metastatic disease is incurable and causes 90% of breast cancer-related deaths. Current treatments for breast cancer help patients live longer, but they have no effect once the tumor is in the brain. Moreover, by prolonging survival they increase the risk of brain metastasis over time.
Primary breast tumors secrete factors that travel through the blood and facilitate seeding and growth of new distant tumors by inducing changes in the structure of other organs. The proposed research will look at how regulatory T (Treg) cells, a type of immune cells heavily present in primary tumors, support changes in the brain tissue that allow brain metastasis to develop. To model this, we will utilize genetically engineered mouse models and surgical manipulations like the ones occurring in human breast cancer patients to investigate how the presence of regulatory T cell affect brain metastasis formation over time. Specifically, we will assess the changes in cell composition and structure of the brain tissue before metastasis develops in mice with and without Treg cells. In addition, we will evaluate changes in blood circulating factors, and establish the requirement of cells from the bone marrow and specific cytokines for the remodeling of the brain. By learning more about what happens to the brain tissue before metastases form, we hope to improve our chances of developing therapeutic strategies to prevent them.
Lung cancers are often driven by genetic changes. The focus of my research is on a type of lung cancer that is driven by changes in the EGFR gene. This type of lung cancer often occurs in younger patients who are non-smokers. New medications can target these changes. This has allowed patients to live longer. However, patients are almost never cured of their disease. My goal is to understand why responses to these EGFR targeted treatments are almost never curative. Then I will work to identify new medications that can be used together with EGFR inhibitors. This may allow patients to live longer. I will accomplish this goal by identifying all of the genetic changes present in patients’ tumors. This will allow us to understand which ones may be allowing cancer cells to survive. I will also assess tumors for other changes that occur within cancer cells. In addition, I will look at the immune cells that are in the tumor. To summarize, the goal of this research is to identify new combination therapy strategies that can improve the depth and duration of response to EGFR targeted therapies, allowing patients with this deadly disease to live longer.
Funded in partnership with the SAGERSTRONG Foundation in memory of Craig Sager
There are trillions of bacteria, viruses and fungi inside each and every human. We call this the microbiome. Scientists have found that the microbiome can change how cancer grows and how people respond to cancer therapies. Our lab wants to make the lives of cancer patients better by improving their microbiomes. The usual ways to change the microbiome are through diet, antibiotics, and by eating live bacteria in food. An example of a food with live bacteria is active culture yogurt. We are doing an experiment to see if a special type of fiber can improve the human microbiome. This fiber is digested by specific bacteria in the gut. When it is digested, it is turned into molecules that control the human immune system. We are giving cancer patients this fiber to see if we can increase these immune system-controlling molecules. If this works, we will prevent the immune system from doing harm in cancer patients. We hope to help patients like those who get blood and marrow transplants for treatment of leukemia or lymphoma. Once we understand how these fibers and our microbes change the immune system, we can figure out precise ways to use this knowledge to make the immune system work better. For example, we may be able to make exciting new cancer therapies, like immunotherapy, work better.
Age is the greatest risk factor for breast cancer. About 80% of all breast cancers occur in women older than age 50. Aging is associated with tissue changes as well as changes in the genes that are expressed in breast cells. However, the age-related molecular and cellular mechanisms that underlie these changes and contribute to breast cancer development remains poorly understood. Our lab studies a mechanism by which genes are read to produce different proteins, called RNA splicing. RNA splicing can generate proteins with different functions from a single gene. We previously discovered that this process is altered in human tumors and leads to breast cancer. Additionally, changes in RNA splicing also occur in healthy aging. Here we will test the hypothesis that (1) changes in RNA splicing occur in the mammary tissue with age, and (2) that these splicing changes prime the breast for tumor formation. Our research findings may provide biomarkers of breast cancer risk before the tumor develops. Our ultimate goal is to identify novel strategies for early breast cancer detection, early intervention, and prevention.
Funded by the Stuart Scott Memorial Cancer Research Fund
Pancreatic cancer is a deadly disease. Most patients with pancreatic cancer are diagnosed at late stages. There are no impactful treatments for this disease. Patients with advanced disease only survive for a few months. There is a need for novel approaches for novel therapies. We need to understand the biology that allows cancer cells to create new tumors and invade other tissues. We propose to study the role of a new RNA modification. These changes on RNA control many aspects of the cells. Recently, the proteins that modify the RNA have been involved in several cancer types. However, the way that they act in cancer cells is unknown. We propose that the RNA changes are used by cancer cells to increase their ability to grow and invade new tissues. Thus, we propose to use multiple approaches to test the role of this RNA modification in pancreatic cancer initiation and progression. Understanding the basic mechanisms involved in the abnormal use of this RNA changes could lead to the development of novel therapies to treat cancer and metastatic diseases.
Diffuse large B-cell lymphoma is a blood cancer that is currently treated with chemotherapy drugs. These drugs can be toxic, and do not work for all patients. Certain cancer-causing genes must be turned on in order for lymphoma cells to grow and survive. One new way to treat patients with lymphoma might be to find drugs that turn off the ‘switches’ that cancer cells use to turn genes on. This could potentially kill cancer cells without hurting normal cells.
We will study the proteins and DNA code that serve as a ‘switch’ to control two lymphoma-promoting genes, MYC and BCL6. We will use new technologies to learn how these genes are turned on, and how we can block this process. Some lymphomas contain errors in the DNA code (mutations) that alter these gene ‘switches’. We will compare the function of lymphomas with mutations to lymphomas with intact ‘switches’.
This project has two main goals. First, we seek to create new tests that can be used to find mutated gene ‘switches’ and guide lymphoma patient care. Second, we seek to find target proteins that could be used to create new lymphoma treatments.
Over the past several decades, there has been a steady increase in cure rates in children with the so- called B-cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer. Yet many B-ALL patients who failed the initial chemotherapy still die from their disease. Five years ago many of these high-risk patients began to benefit from immunotherapy, whereby patients’ own immune systems are trained to recognize and destroy the leukemic cells. One common form of immunotherapy is based on recognition of CD19, a protein residing on the surface of most leukemic cells. However, even this breakthrough treatment fails in about a third of patients, suggesting that other leukemia proteins need to be targeted in parallel. One alternative protein target is called CD22. CD22-directed immunotherapies show promise, but are not without their own record of failures. Our previous studies led us to believe that one common cause of treatment failure is improper assembly of the CD22 protein, resulting in re-shuffling of its key parts called ectodomains. This re-shuffling could result in CD22 becoming unrecognizable to the immune system. On the other hand, improperly assembled CD22 could be targeted using a new type of immunotherapeutics, which are trained to recognize improper junctions between ectodomains. The proposed work will test these ideas using leukemic cells grown in Petri dishes and in mice and samples from ongoing clinical trials. It will also extend our current studies to other cell surface proteins. In the end, the TVF-funded work would lead to a more precise matching of future patients to best possible treatments and thus much better outcomes.
First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Suzanne Pride Bryan
Approximately 20-25% of breast cancers express the human epidermal growth factor receptor 2 (HER2). These tumors are associated with a high risk of recurrence because of possible resistance to HER2-therapies. Therefore, new therapies are needed to treat this fast growing form of breast cancer.
Poly (ADP-Ribose) polymerases (PARP) inhibitors have been used to treat breast and ovarian cancers with DNA mutations. In addition to its roles in DNA damage repair, PARP1 has other roles such as activation of genes, which control tumor cell growth. PARP inhibitors may be used as a treatment to block tumor cell growth. In this study, we will determine the safety and effectiveness of combining the PARP inhibitor niraparib with the HER2-targeted agent trastuzumab to treat HER2+ breast cancer in a clinical trial. We will also examine tumor tissue samples to help us understand how the treatment effects tumor response. Our goal is to develop better therapies to improve the survival of breast cancer patients who are at high risk of relapse.
JMML is a type of blood cancer that affects infants and young children. The cancer cells cause children with JMML to experience belly pain, have difficulty breathing, and be more likely to have bleeding problems. The only way to cure JMML is to kill off every blood cell using harsh medications, and then use someone else’s healthy blood cells as a replacement, known as a stem cell transplant. This treatment causes many side effects like vomiting, hair loss, and can lead to serious infections. Equally upsetting is that this intensive treatment only works half the time with few children surviving if the transplant does not work.
Over the past several years, we have developed lab tests that predict which patients are likely to respond or not respond to this type of intensive treatment. The first aim of this grant is to turn our research test into a clinical test that can be ordered by any doctor around the country to help them decide how to treat their patients with JMML. Our second aim to test two different, new and safer medications in mice to see what the best way is to combine them. Lastly, the overall goal of this grant is to start a trial that uses the clinical test that we described in our first aim to help pinpoint the patients that will benefit from the two medications in our second aim. We expect that by adding these medications we will improve the lives of children with JMML.
