Funded through the Stuart Scott Memorial Cancer Research Fund by John and Michele Truchard in honor of Jo Ann Truchard
Colorectal cancer is the second most common cause of cancer-related death in the United States. New research shows that colorectal cancer cases are increasing in younger age groups. We know that obesity is a major risk factor for colorectal cancer rates among younger adults, but we still don’t understand exactly how it works. Our research goal is to answer this important question. Obesity is mostly caused by unhealthy eating habits, including eating a diet rich in “bad fats”. First, we want to understand how healthy cells are damaged by “bad fats”. This is important because damages cells can produce harmful substances that cause cancer. “Bad fats” may also produce substances that feed harmful bacteria living in our intestines. These bacteria produce toxins that cause cancer. We will try to understand how the bad bacteria use this “food” to grow in the gut of obese individuals. This will help us show that “bad fats” cause cancer both by damaging cells and by feeding cancer-causing bacteria. If successful, our work will show how the dietary habits that lead to obesity can also cause colorectal cancer by damaging cells and feeding the growth of harmful bacteria. These findings will help us find new treatments for patients suffering from cancers caused by obesity.
Funded by the Tyler Trent Fund and the Dick Vitale Pediatric Cancer Research Fund
A critical failure in the field of pediatric thyroid cancer care is the use of adult treatments for a childhood disease that has distinct genetics and tumor behavior. With thyroid cancer incidence rapidly increasing, we need to develop personalized treatments for this population to ensure their long and productive lives. There is currently no way to predict which children will go on to develop recurrent or aggressive disease at the time of biopsy and thyroid surgery. While thyroid cancer is generally curable, adolescents and young adults present with more frequent local and metastatic disease when compared to older adults. Adult treatment protocols lead to high cure rates, but adolescents and young adults have many years of potential recurrence, radioactivity-induced side effects, and secondary malignancies ahead. Precision medicine is becoming the standard of care for many diseases except pediatric thyroid cancer.
To develop more individualized pediatric thyroid cancer care, the scientific community must first strive to better understand the mutations and abnormal cellular signaling responsible for thyroid cancer behavior. Our research program utilizes a large cohort of adolescent and young adult human thyroid tumors in order to study the signaling pathways responsible for the unique growth and spread of each tumor. The funds from the Pediatric Cancer V Scholar Award will lead to an improved understanding of thyroid cancer development in this population and innovative therapies for children with this disease. These treatment strategies can then be applied to a wide range of pediatric cancers with reliance on similar signaling pathways.
Year one is partially funded by UNICO in memory of Toni Alongi
Survivors of childhood leukemia (ALL) who are treated with chemotherapy develop poor cognitive skills (e.g. attention, speed of thinking, reasoning). These poor cognitive skills cause problems with school, work and peer interactions. The survivors also display abnormalities on brain imaging. We demonstrated that fluid collected during a spinal tap (i.e. cerebrospinal fluid [CSF]) contained markers of brain injury. However, our initial study was too focused on specific brain cells. We could not identify the cause of the brain injury. Thus, we want to conduct another study to examine many more protein markers before and after chemotherapy treatment.
We will use an advanced process to identify over 4,000 proteins in the CSF. This will permit us to determine the cause of the brain injury. We will compare the proteins to sex and age of the survivors. We will also compare the proteins to the treatments the survivors got. Finally, we will compare the change in proteins to brain imaging and cognitive testing.
CSF samples from a recently completed trial have been collected and frozenat −80°C so they will not decay. The brain imaging and cognitive testing is currently being completed as part of an institutionally funded protocol. For the current project, we will process the CSF samples and link them to adverse events and clinical outcomes.
With this comprehensive approach, we will identify which survivors are at greatest risk, and identify targets to prevent brain injury in future clinical trials.
Primary liver cancer is a leading cause of cancer death worldwide. Liver cancers are resistant to many cancer drugs. Our immune system has enormous power to find and destroy infectious microorganisms in our bodies, and scientists reasoned that immune cells such as T cells could also find and destroy cancer cells. Using a mouse model of liver cancer, we found that T cells could recognize cancer cells in the liver, however the T cells failed to kill the cancer cells. We discovered that interactions between liver cancer cells and T cells quickly restructured T cells’ DNA. DNA is the program that controls how cells respond and function. The DNA restructuring in T cells took away the T cells’ ability to kill cancer cells. Our goal is to understand how the interaction between liver cancer cells and T cells makes T cells dysfunctional. We are working to develop a three-dimensional liver cancer model in cell culture dishes. We can add T cells to precisely study the earliest changes in T cells after they encounter a liver cancer cell. This will give us clues about why the T cells are shut down their anti-tumor function. We will then test DNA targeting strategies to see if they prevent T cells from becoming dysfunctional. Ultimately, these genetic targeting strategies can be used to activate T cell responses against cancer cells in patients with liver cancer.
The research supported in this proposal will impact patients with ovarian cancer. Ovarian cancer is the most common cause of gynecologic cancer death. Noninvasive imaging is critical for detecting disease and monitoring response to treatment. However, current methods are inadequate and better approaches are urgently needed. Our concept is that the protein cyclooxygenase-1 (COX-1), which is expressed at high amounts in ovarian cancer, can be used to detect and monitor the spread of disease and response to treatment. We will test a first-of-its-kind COX-1 targeted PET molecule in mouse models of ovarian cancer. Our study paves the way to clinical trials of a much-needed new imaging technique to benefit women diagnosed with ovarian cancer.
The overall purpose of our research project is to identify if there are patterns of genetic changes (i.e. mutations) that explain why some children with acute myeloid leukemia (AML) fail to effectively respond to chemotherapy and ultimately relapse. Relapsed disease is strongly associated with poor outcome and early death in children with AML. Frequently, when AMLs relapse they do so through the outgrowth of a cell population (subclone) that was present at a low level at the time of diagnosis. These subclones frequently have mutations that allow them grow better after therapy. Unfortunately, we have a poor understanding of these subclones in pediatric AML and methods to detect them and study them are lacking. The proposed studies in this grant will identify these mutations in a large group of relapsed pediatric AML and then address if sensitive approaches to detect mutations in patients after therapy will increase our ability to predict relapse. Currently our methods to predict relapse are not applicable to all cases and likely do not effectively capture all leukemic subclones for analysis. In the second part of this grant we propose a model system to introduce mutations that will allow us to more effectively study the subclonal complexity of AML to understand why some subclones are more resistant to chemotherapy. Collectively these studies will dramatically increase our understanding of pediatric AML with the long-term goal of pushing the outcomes of pediatric AML closer to pediatric ALL.
