Lung cancer is a deadly disease. This lethality is due, at least in part, to how often and how extensively these cells can spread throughout the body. My laboratory is working to understand what causes these cancer cells to spread and how they survive this process. By doing so, we hope to identify new ways to treat lung cancer.
We are interested in the nutrients cancer cells use to support growth and how these nutrients might help cancer cells spread. We are particularly interested in fats, or fatty acids. These complex nutrients play many different roles in cells, including helping to maintain cell structure, storing energy, and even acting as a method of communication with other cells. When we measured fatty acids in lung cancer, we saw that several fats and fatty acid pathways were different in tumors that spread throughout the body, compared to tumors that did not. In this study, we investigate how fatty acid metabolism supports aggressive cancer cells, and we will test whether blocking these fatty acid pathways can prevent lung cancer cells from spreading.
Funded by the Dick Vitale Pediatric Cancer Research Fund and the StacheStrong Foundation
Clinical outcomes in children diagnosed with high grade glioma and diffuse intrinsic pontine glioma remain very poor. Even with surgical resection, chemotherapy and radiation, most of the tumors eventually relapse. This is primarily because some cancer cells develop resistant to the therapies that doctors prescribe. For the past 50 years, the identities of these therapy-resistant cancer cells remain unknown. Difficulties of obtaining relapsed tumor tissues and limited availability of animal models are the major reasons why we still don’t have new treatment. With the strong support of patients and families, we have developed a panel of animal models by directly implanting brain tumor cells into the brains of immunodeficient mice. We can now use these models to mimic what happens in children but treating the animals with the similar drugs/radiations. These models are very helpful. Indeed, our preliminary study in a small number of models have identified a set of cells expression CD57 as candidate root cells as they were found before drug treatment, remain present after very extensive clinical treatment, and can even survive the most harmful environment with no oxygen and no nutrient. This exciting finding has promoted us to perform a detailed analysis using more animal models to confirm the extraordinary capacity of the CD57+ cells in resisting therapy induced cell king, to understand how they can survive current treatment, and to find new drugs and strategies to selectively kill these seed cells. Our ultimate goal is to find new cure for children with highly malignant gliomas.
Funded by the V Foundation Chicago Epicurean in honor of Marc Silverman and in memory of Jeff Dickerson
Cells require nutrients to fuel their metabolism to sustain life. Healthy tissues are fed nutrients by blood vessels in a process called perfusion. In contrast, cancers have dysfunctional blood vessels. Compared to normal tissues, blood vessels dysfunction in tumors limits perfusion. This limited perfusion results in abnormal nutrient levels in tumors. We have found that abnormal nutrients in pancreatic tumors blocks the ability of chemotherapeutic drugs to kill pancreatic cancer cells. This is an important finding as pancreatic tumors are resistant to chemotherapeutics, which causes high mortality in this disease. We propose that: (1) identifying the nutrients in pancreatic tumors and (2) how these nutrients lead to chemotherapeutic resistance could lead to new treatments to improve patient chemotherapy outcomes. These are the two critical goals of the proposed project.
To identify the metabolic stresses in tumors that cause chemotherapeutic resistance, we searched for nutrients in tumors that cause chemotherapy resistance. We found that certain amino acids accumulate to high levels in tumors and cause chemotherapy resistance. We will determine if blocking tumor accumulation of these amino acids can improve the chemotherapeutic treatment of pancreatic tumors. Toward the second goal of identifying how amino acid accumulation causes therapy resistance, we will use advanced biochemical and genetic tools to determine how the amino acids accumulating in tumors enable pancreatic cancer cells to survive chemotherapy treatment. Completing aims will provide new insight into how nutrients in pancreatic tumors cause chemotherapy resistance and provide clinically actionable approaches to improve chemotherapy response in patients.
Funded with support from The Orr Family Foundation
Lung cancer is the most common source of cancer-related death in the U.S. and worldwide. Lung cancer is a heterogeneous disease, with multiple subtypes characterized by different genetic and molecular profiles, and different response to treatment. One subset of lung cancer is caused by the loss of a gene called LKB1, and approximately 50,000 people are diagnosed with this type of lung cancer in the U.S. each year. Currently, no available therapies elicit sustained clinical benefit for patients with LKB1-mutant lung cancer, and the current overall survival time for such patients from the time of diagnosis is less than one year. Thus, there is great unmet need to rapidly discover and translate clinical options to help these patients. Our recent work has discovered a mechanism of therapeutic resistance (an explanation why tumors do not respond to therapy) that is specific to LKB1-mutant lung tumors. We discovered that two available, clinically-tolerated drugs together can overcome this mechanism, and we are working toward clinical translation of this finding. However, we predict that this finding is only the tip of the iceberg, and that we are poised to discover additional promising therapy approaches as well. Therefore, it is now imperative to fully characterize the mechanisms of therapeutic resistance in this tumor type, as we will do in this project, to expand our understanding of how to treat patients with this disease. The hope is that this study will pave the way toward improved therapeutic options for patients with lung cancer.
Co-funded by the Dick Vitale Pediatric Cancer Research Fund and the Jeff Gordon Children’s Foundation
Children with cancer are typically treated with chemotherapy to kill all dividing cells, including tumor cells. This general treatment causes side-effects, including damaging the normal healthy cells children need to grow and thrive. An additional, devastating, long-term side-effect of the use of chemotherapy is the risk of developing a second cancer. To circumvent these toxicities, we propose a targeted treatment tailored for a subset of pediatric patients with blood cancer. We identified a gene called “CUX1” that is deleted in the blood cells of patients with certain types of leukemia. Loss of one copy of CUX1 causes blood cells to grow too fast and stop maturing. In the current proposal, we predict that a drug that increases CUX1 levels will prevent leukemia growth and restore normal blood cell maturation. The objectives of the current proposal are to identify druggable regulators of CUX1 and to use these compounds to restore CUX1 in leukemias with CUX1 loss. We have identified one candidate regulator, named GSK3. We hypothesize that inhibition of GSK3 will increase CUX1 levels, halt leukemia growth, and restore normal blood development. We will accomplish these studies using innovative genetic screening, novel mouse models of childhood leukemia, and patient leukemia samples. Accomplishing the proposed studies will aid in the development of non-toxic therapies for children. This work will help us achieve our long-term goal of devising urgently needed treatments to improve the outcome for high-risk leukemias of childhood.
Funded by the Stuart Scott Memorial Cancer Research Fund
Liver cancer is a leading cause of cancer-related deaths. Its incidence continues to increase, posing a significant threat to public health. A leading risk factor is the chronic exposure to liver stress, which, in turn, enhances the uncontrolled division of cancer cells and tumor growth. Proteins are the functional units within cells. They are made from the instructions stored in DNA and carried by messenger RNA (mRNA) through a process known as translation. Notably, the information stored in DNA is not static and can be modified to alter the outcome of translation to promote cancer growth. Two of these modifications are called ‘RNA oxidation’ and ‘RNA acetylation’, which are induced in liver cells in response to cellular stress, and their levels correlate with tumor growth. Thus, this study will investigate how the interplay between RNA modifications and translation promotes liver cancer. The results obtained in this study will allow for future clinical efforts to fight liver cancer.
The cells in the human body are constantly subjected to stress, which is linked to changes in cellular metabolism. Our research team, and others, have made connections between these cell conditions and cancer. Our central question is: Can we make a simple blood test that provides an accurate measure of ongoing cell stress and metabolic changes to gauge an individual’s risk of cancer? This test may provide more than just a snapshot measure of cancer risk. For example, the test could be used to measure how lifestyle changes modify cancer risk across the lifespan. To answer our question, we developed expertise that enables rapid measurement of signals in certain blood cells attributed to changes in cell stress and metabolism. Our study will determine if these signals can be used to quantify cancer risk. We will obtain blood samples from individuals without cancer, from individuals who have a condition known to increase their risk of cancer, and from individuals diagnosed with cancer. We will isolate certain cells from these samples and then measure the candidate signals in the cells. We anticipate our studies to reveal that the signals we are measuring will be the lowest in healthy individuals, will increase in individuals with the precancer condition, and will be highest in people diagnosed with cancer. These findings would powerfully validate our technology and suggest that individuals may benefit from our test for the early detection, and even prevention, of cancer.
Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck cancers worldwide. Finding OCSCC early, when it’s small and hasn’t spread, allows for more successful treatment, and increases patients’ survival. Unfortunately, most of the patients present at advanced stage when diagnosed. Current method for OCSCC diagnosis (which includes cutting of tissue for laboratory testing), is invasive, costly, and depends on examiner experience, underscoring the need for developing noninvasive cancer detection methods. As OCSCC grows, it accumulates mutations in genes known to play role in cancer progression. Our group and others have reported that such mutations can be detected in saliva of patients with OCSCC. However, no saliva-based screening method for early detection of cancer are currently available. Recently we have developed a method based on the targeted sequencing technology specifically designed to detect OCSCC-associated mutations in saliva and validated this assay using specimens collected in India (a country with a high incidence of OCSCC). While these findings provide the foundation for using this ultra-sensitive and cost-efficient assay in clinical settings, frequency of cancer-driving mutations may vary in patients from different ethnical backgrounds. Our proposal will leverage the unique geographic location of the University of Chicago to evaluate the performance of this test across demographically heterogeneous patient populations, as well as across diverse therapeutic approaches for treatment of OCSCC. A well-validated, saliva-based cancer detection assay with optimal analytical performance would represent a significant clinical advancement in cancer care by reducing mortality, while lowering the socio-economic burden of OCSCC.
Merkel cell carcinoma (MCCs) is a cancer that requires additional research. It is the most deadly skin cancer. Moreover, its incidence is rising, doubling from 2000 to 2013. Until recently, there have been no effective therapies for this disease. Immunotherapies have revolutionized the treatment of MCCs. Roughly 50% of patients respond to these treatments, called PD1 inhibitors. While this is an important advance, there are critical barriers to cure. There are no biomarkers to predict who will respond to treatment. Moreover, there are no treatments for patients who fail immunotherapy. To address this critical unmet need, we have assembled a large clinical cohort of patients with MCCs across multiple institutions. We will subject them to a number of assays designed to identify what immune cells are in each sample and what they are doing. Our goal is to identify patterns that predict who responds to therapy and why or why not. The biomarkers we discover can be immediately deployed to ensure that PD1 inhibitors are only given to patients likely to respond to them. For the rest, our studies will seek to identify novel immunotherapy drug targets. If successful, we can develop new drugs that can be used against these novel targets and test them in future clinical trials. This knowledge will be critical to improve patient care and a key advance to developing a cure for this deadly disease.
The treatments for head and neck cancers have been revolutionized by the development of immunotherapies. However, many treated cancer patients often experience relapse. Without a clear understanding of why and how cancer cells resists and relapses after current immunotherapy treatment, it is impossible to design a better immunotherapy, and the current treatments for cancer patients eventually fail due to relapse. For advancing clinical outcomes of future treatments, the goal of this proposal is to identify key mechanisms driving cancer relapse from immunotherapy. Recently, we discovered a special group of tumor cells that resemble the stem cells responsible for regenerating normal tissues. Importantly, these tumor cells appear to be the major survivor of immunotherapy treatment and the cause of tumor relapse. This key finding raised the possibility of targeting the critical molecular programs driving the unique immune resistance of these special cancer cells to prevent cancer relapse. In this study we will develop a new immune-oncology platform for head and neck cancer, so we can achieve rapid genetic manipulation of cancer cells directly in live mice. With this powerful approach we aim to identify the stem cells-specific factors that govern both intrinsic and extrinsic immune resistance mechanisms in head and neck cancer. The information derived from this study will pave the way to the development of the next generation of immunotherapy for head and neck cancers with the capacity to overcome relapse.