Kidney cancer is the 8th most common cancer in the USA, representing 3% of new cancer cases each year and 4% of cancer deaths. Renal cell carcinoma (RCC) is the most common and lethal type of kidney cancer in adults, representing 90-95% of all kidney cancer cases. Approximately 90% of RCCs have mutations in the tumor suppressor gene, von Hippel-Landau (VHL), which is involved in the degradation of hypoxia-inducible factor (HIF) transcription factors. The mutation of VHL leads to huge increases in the levels of HIF, which promotes tumor growth by increasing the blood supply to tumors. Uncovering this pathway of tumor suppression has led to several targeted therapeutics that lower levels of HIF, and are currently used in the clinic. While this has improved the outcome for RCC, the median survival rate for metastatic renal carcinoma patients is still only 22 months. Uncovering additional mechanisms of tumor suppression and new therapeutic targets would bring us closer to our goal of eradicating these cancers. To this end, efforts to identify additional genes mutated in RCC have identified Polybromo-1 (PBRM1) as the second most commonly mutated gene in RCCs (~50%). PBRM1 is part of the SWI/SNF (BAF) chromatin remodeling complex, an important regulator of gene expression. While subunits of the BAF complex are mutated in a spectrum of cancers, mutations in PBRM1 seem to be fairly specific to RCC. We aim to understand the mechanism of tumor suppression by PBRM1 in RCC by 1) uncovering how PBRM1 deletion affects the function of the BAF chromatin remodeling complex, 2) identifying genes regulated by PBRM1 deletion, and 3) identifying pathways important in RCC progression that we can target with novel or known therapeutics.
Each year, in the U.S. alone, over 50,000 people are diagnosed with myeloid cancers of the blood. Some myeloid cancers have been found to lose all or a portion of chromosome 7 [-7/del(7q)], and these cases are particularly difficult to treat. The overall survival for these patients is less than one year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms/cancers (t-MN). t-MN arise as a side effect of chemotherapy/radiation and occur in u to 8% of cancer survivors. There is clearly an urgent need to develop better therapies for -7/del(7q) disease. It has long been thought that one or more genes on chromosome 7 prevents cancer growth – “tumor suppressor genes.” I used genomic technologies and animal models to map this tumor suppressor gene, implicating CUX1. The long-term goal of the current proposal is to improve the outcome for patients with this type of disease. This proposal is designed to accomplish this by identifying CUX1-regulated pathways that may be potential drug targets as well as establish animal models for future use in preclinical therapy development. The contribution of the proposed research is expected to bhe characterization of the biological outcomes and altered pathways caused by CUX1 loss–the first step toward developing therapies. The significance of this work is not limited to leukemia; CUX1 is mutated in endrometial cancer, gastric cancer, and melanoma, among other tumors. Thus, the understanding of CUX1 function in myeloid disease may guide our knowledge of the role of CUX1 in other cancers.
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.
Abeloff V Scholar * (Tie for Top Rank)
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.
Immune-based medicines are effective in treating and curing subsets of patients across multiple cancers. However, approximately 80% of patients across all cancers fail to respond to immune-based medicines. This lack of clinical benefit is particularly prevalent in aggressive forms of metastatic prostate cancer (MPC) that are resistant to hormonal therapies, where few objective responses to immune-based medicines have been observed.
The immune system is comprised of cells that can both promote and suppress the growth of the cancer. Our research has revealed that the microenvironment within MPC exhibits scarcity of immune cells. Furthermore, the sparse immune cells that reside within the microenvironment of MPC promote tumor growth and progression. Therefore, there is an urgent need to develop medicines that reprogram the tumor-promoting “bad” immune cells to create a more favorable environment, so the “good” immune cells can enter the tumor and kill cancer cells. The goal of our research is to identify and develop new medicines that can achieve this “switch” in the immune system, to enhance recognition and elimination of the most aggressive forms of prostate cancer. We will test these potential medicines in both mouse models of PC in the laboratory, and in patients with the most aggressive forms of MPC enrolled in clinical trials. Collectively, the findings stemming from this proposal will lead to a deeper understanding of the immune escape mechanisms that allow MPC to spread, and advance the clinical development of novel medicines to reinvigorate the body’s immune system to eradicate MPC.