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.
Synovial Sarcoma is a cancer that affects 800 Americans every year, generally teenagers and young adults. Although it can be cured if caught early, it often spreads though-out a patient’s body making it very difficult to eradicate. A new type of therapy, known as immune checkpoint inhibitors, can unleash anti-tumor immune responses against many types of cancer. But these treatments are not effective against Synovial Sarcomas. We think this is because immune cells rarely enter the tumor, and the few immune cells that are nearby cannot “see” the tumor. We have worked to address this barrier and our early findings suggest that combining checkpoint inhibitors with an old drug called interferon gamma can empower immune cells to eliminate Synovial Sarcoma.
In our new project, we will test the interferon + checkpoint inhibitor combination in a clinical trial. Using tumor and blood samples from patients, we will perform a thorough analysis of both tumor and immune cells in order to learn how to make this therapy work better and for even more patients. While Synovial Sarcoma is a rare cancer, there are other cancer types that seem to be resistant to checkpoint inhibitors for similar reasons, and our findings will likely be broadly applicable.
Working outside the regular hours of 7am to 6pm, or shift work, has become a critical component of our 24-hour society. With approximately 18% of workers in the US engaged in shift work, the possibility that working at night causes cancer is an important public health issue. While increased cancer risks have been observed among shift workers, the specific factors responsible for the increased risks remain unknown. Identifying these factors is crucial to the development of strategies to prevent cancer among shift workers. Sleep disruption is thought to be a likely causal factor, but little research has been done, and studies thus far have relied on crude measures of sleep disruption. By looking at DNA damage among shift workers and using detailed measures of sleep quality, our study will, for the first time, closely examine the cancer causing role of sleep disruption among shift workers. Though sleep disruption occurs commonly among shift workers, it is not unique to them, so findings from this study will be broadly useful to the protection of health and well-being across the general population.
V Scholar Plus Award – extended funding for exceptional V Scholars
Our research is important because we study a new uncharted realm of gene expression in cancer call mRNA translation. This significantly understudied field is poised to reveal new insights into what makes cancer so difficult to treat and identify completely new ways to treat them. Our laboratory has developed new technologies to study this process in cancer. For example, we specifically focus on late stage prostate cancer which leads to approximately 26,000 deaths per year in the United States. Through the generous support of the V Foundation, we have developed a tool box of advanced staged prostate cancer models and have discovered that mRNA translation plays a key role in this disease. Furthermore, we have developed new sequencing based technologies to study the parts of the human genome which regulate mRNA translation in cancer. Importantly, we are rapidly discovering that our work applies not only to prostate cancer, but to all human malignancies. Ultimately, we aim to develop new drugs to target mRNA translation. If we are successful we will break open completely new ways to think about and treat incurable cancers.
Metastatic breast cancer is a result of breast cancer cells that spread to and grow in other organs. It is one of the most feared consequences of breast cancer, and the main cause of death from this disease. Yet, we still do not know what causes breast cancer cells to spread and become resistant to cancer treatment. For years, researchers have attempted to learn what makes individual cancer cells within tumors most able to migrate and grow elsewhere. My lab recently found that the cells that are the most successful at metastasizing do so as clusters. Clusters are also more resistant to cancer treatment. In this project, we will evaluate the different ways that tumor cells within these clusters communicate with each other. By studying these signals, how they are transmitted and their consequences, we may uncover the key vulnerabilities needed to disrupt and destroy tumor cell clusters. We will take advantage of a technology we invented that allows us to study ‘mini-tumors’ in a dish. We will also analyze the genetic code of the various cell types in the mini-tumors. We will then cross-reference what we learn with very large studies of breast cancer patients. Through shifting our mindset from the individual to the collective, our ultimate goal is to identify new leads for the development of therapies to treat – or prevent- metastasis so that we can save lives.
