Few words inspire more fear than “pancreatic cancer,” which is the third leading cause of cancer death in the United States. Treatments have changed little over recent years despite the fact that researchers have learned a great deal about the genetic mutations that give rise to pancreatic cancer. One challenge is that there are different “subtypes” of pancreatic cancer, thereby making a one-size fits all approach difficult. Tailored therapeutic approaches are desperately needed. While studying pancreatic cancer subtypes, our lab identified that drugs which block a protein called cyclin-dependent kinase 7 (CDK7) could selectively kill the most lethal subtype of pancreatic cancer at extremely low doses. This subtype, referred to simply as basal, makes up ~25% of pancreatic tumors and has the worst overall survival. Further, because the drug works at such low doses, we may be able to treat patients at doses that do not cause significant toxicity. Here, we propose to study a drug that inhibits CDK7, in patients with early-stage pancreatic cancer following chemotherapy and before surgery. Concurrently, we will test new pancreatic cancer treatment strategies and drug combinations in mouse models of pancreatic cancer. We will validate and search for new blood markers of treatment response and drug resistance. Finally, we will identify pathways that allow cancer cells to survive CDK7 inhibition and determine whether other drugs can be added to enhance this therapy. The ultimate goal of our research is to provide a new targeted treatment option and hope to pancreatic cancer patients.
Funded by the Stuart Scott Memorial Cancer Research Fund and the V Foundation Wine Celebration in honor of Leo Slattery, 2022 Volunteer Grant Honoree
A big part of the sequences that make our DNA come from viral infections that occurred in the past. These viral ‘fossils’ are typically not active to prevent damage to our genetic material, however in many diseases, including cancer, they are turned on. While it might be logical to think that the activation of these sequences would be a bad thing, evidence suggest that some of these viral fossils were repurposed to perform functions needed for a healthy life. In fact, some viral sequences participate in the formation of the placenta, in the way our genes are activated, and in the way our cells fight other viruses. Therefore, it is possible that the reason we see these viral fossils turned on in cancers is because they are helping the body fight the formation of tumors. Our goal is to test different ways by which the activation of these viral fossils could help prevent and fight cancer. To do this we will search for all the viral fossils present in our DNA, identify sequences that help our bodies find and destroy tumor cells, and test if one special viral fossil is able to prevent tumors by turning off its energy supply. We hope our findings can help the design of novel ways to treat cancer, taking advantage of the potential beneficial roles of these ancient viral sequences.
Research studies that test how new cancer drugs work often don’t include all members of the United States population. Scientists are unable to tell how well these new treatments work in diverse groups. Our team will study how Black cancer patients and their families decide whether participating in a research study is right for them. We will talk with Black cancer patients and their families, doctors, cancer support groups, and Black community members to help us develop a public service video about clinical trials. We will also develop a plan to share information about clinical trials among Black communities. This approach will help us develop a public service video that is based on the needs, experiences, and strengths of Black communities that can be shared widely.
Funded by the Constellation Gold Network Distributors
Every patient’s tumor is different. However, a closer look into a given tumor shows another staggering level of complexity. Like a patchwork, every tumor is made up of individual tumor cells which can show very different behaviors. This diversity makes the diagnosis and treatment of cancers very challenging and is an important reason why some tumors are so difficult to treat. Here we want to shed light on the complex makeup of metastatic prostate cancer. We will study the composition of prostate cancers at the level of single cells. To do this, we will use cutting-edge tools to detect molecular changes in individual cancer cells. This will allow us to better understand how this diversity contributes to the aggressiveness of prostate cancer. Ultimately, our work will help us to provide more accurate and precise diagnoses and more effective treatments for patients with prostate cancer.
While Helicobacter pylori is the major risk factor for development of stomach cancer, only 1-2% of those infected with H. pylori get gastric cancer suggesting the existence of additional necessary factors. We hypothesize the oral bacterium Fusobacterium nucleatum, which normally does not colonize the stomach, can colonized the altered tissue environment created by H. pylori infection to further drive tumor progression. Testing this hypothesis will yield new insight into the mechanisms of bacterial carcinogenesis and highlight new opportunities for intervention.
Our lab is developing treatments for human cancers by engineering immune cells called “T cells” to recognize and kill tumor cells. Engineered T cells can eradicate tumors in patients with blood cancers, like leukemia and lymphoma. However, they have had limited success so far against more common “solid tumors”, like breast and lung cancer, which are responsible for the majority of cancer deaths. Solid tumors can evade attack by inducing T cells to lose function and become “exhausted.” Strategies to preserve T cell function, thus, are needed to extend the success of engineered T cell therapy to solid tumors. Our lab has developed a mouse model of lung cancer that mimics human tumor development and patient response to therapy. In this model, T cells engineered to overexpress a gene that promotes T cell function dramatically eliminated tumors in ~50% of mice. Based partly on these results, a clinical trial is being planned to test whether these T cells are safe and effective in patients. However, our data show that tumors still progress in ~50% of mice. We will use the mouse model we developed to define why tumors progress in a subset of mice and test different combination treatments to identify regimens that improve T cell function and kill tumors most effectively. Working with Fred Hutch clinicians and industry partners, our goal is to translate the strategies that appear most effective in mouse models to the clinic to test their impact in patients.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Colorectal cancer starts in the large intestine. It is the second leading cause of cancer death in men and women in the US. Alaska Native people have among the highest rates of colorectal cancer in the world. Alaska Native people also die more often of this disease than any other racial or ethnic group in the US. The reasons for these health disparities are not fully understood.
Almost no research exists on molecular changes in Alaska Native colorectal cancer tumors. In this study, we will look at the genes expressed in these tumors. Genes code for proteins which support normal cell function. Changes to genes may result in abnormal growth of the cells resulting in cancer. Studying gene expression tells us which genes in the tumor may be causing the cancer and will help us understand more about the patterns of gene expression among Alaska Native colorectal cancer patients. We will also examine if tumor gene expression can tell us which patients will live longer with their cancer.
This research will help to identify colorectal cancer patients with aggressive disease at diagnosis. This could help to guide clinical decision making and improve disease outcomes. Also, this research may tell us if Alaska Native colorectal cancer patients might benefit from available or new treatments.
Funded by the Constellation Gold Network Distributors
My research is focused on understanding the role of genetic abnormalities in prostate cancer treatment resistance. Prostate cancer is one of the most common cancers in men, but what makes prostate cancer deadly in some men, but not others? The answer lies in the DNA of prostate tumor cells. Abnormal changes can occur in the DNA of tumor cells and give them the ability to resist standard treatments. Monitoring tumor DNA over time could uncover these changes. As the cancer progresses, tumor cells can move and grow in distant organs. Often, obtaining tumor cells from these organs is painful and difficult. What if tumor cells and its DNA were easier to access? We address this problem by using an exciting method, called a “liquid biopsy”, to measure tiny amounts of DNA that are released from tumor cells into the blood. We develop new computational techniques, combined with genetic sequencing, to reveal “signatures” of tumor DNA alterations from the blood. These signatures could allow oncologists to track whether a patient is responding well to treatment. They could also help predict whether a patient’s tumor has the potential to resist treatment. Ultimately our work will provide new tools to help doctors care for patients with less discomfort, more accuracy, and greater precision.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Hematopoietic cell transplantation (HCT) can cure cancer in many patients, but some survivors will develop a devastating complication calledbronchiolitis obliterans syndrome (BOS). BOS causes debilitating scar tissue in the lungs. Patients with BOS can experience shortness of breath, lung infections and long-term breathing problems. Some patients will die from BOS. BOS is hard to treat because most patients are diagnosed with after permanent damage has been done. If we can diagnose BOS earlier, before patients have symptoms, we might be able to prevent suffering. HCT patientswho have a condition calledchronic graft-versus-host disease, in which donor cells attack the patient’s tissues,are more likely to develop BOS. Our study will enroll patients with chronic graft-versus-host disease and test whether a simple tool called a spirometer can detect the earliest signs of BOS. We will give study participants a handheldspirometertomeasure how well a participant’s lungs are functioning. During the study, participants will use the spirometerevery week at home.The spirometer connects to the participant’s smartphone. The results will be sent to the study team over internet. If the team sees that a participant’s lung function begins to decline, the participant’s doctor will be informed.We hope that this tool can help a patient’s doctor diagnose and treat BOS earlier. Our ultimate goal is to ensure that patients who survive cancer also thrive after their treatment.
Few words inspire more fear than “pancreatic cancer,” and for good reason. Pancreatic cancer is the third leading cause of cancer death in the United States and treatment regimens have changed little, despite these poor outcomes. Researchers have learned a great deal about the genetic mutations that give rise to pancreatic cancer. Yet, we still struggle to apply this information towards more effective treatments. An enormous challenge is that there are different “subtypes” of pancreatic cancer, which makes designing tailored treatments complicated. While studying individual pancreatic cancer subtypes, our lab identified a drug that can selectively kill the most lethal subtype of pancreatic cancer at extremely low doses. This subtype, referred to simply as QM, makes up ~25% of pancreatic tumors and has the worst overall prognosis of all subtypes. Further, because the drug works at such low doses, we may be able to treat patients at doses that do not cause significant toxicity. Here, we propose to define the details of how this drug kills QM pancreatic cancer cells. We will also test whether it can treat pancreatic cancer in mouse models. Finally, we will identify ways that cancer cells could develop resistance to this drug, a frustratingly common outcome. What we learn could help to develop modified versions of the drug or possible combination regimens to overcome resistance. The ultimate goal of our research is to identify new therapies that can be tested in clinical trials.
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