Grant Archive - Page 43 of 136

Ulrich Steidl, MD, PhD

Partially funded by the Stuart Scott Memorial Cancer Research Fund and the V Wine Celebration in honor of First Responders

Nick Valvano Translational Research Grant*

Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) originate from abnormal blood stem cells which have acquired multiple molecular aberrations over time and generate the bulk tumor cells that are diagnosed in patients in the clinic. Conventional therapies inhibit the bulk tumor cells; however, they do not eliminate the early blood stem cells that are the true root of the disease. Recent work has uncovered unexpected diversity of stem cells in patients with MDS, detected through a new methodology which we recently developed. Cancer/leukemia development is, at least in part, promoted by exposure to environmental toxins. The terrorist attacks on the World Trade Center created an unprecedented environmental exposure to aerosolized dust and gases that contained many carcinogens, and over the past few years we have built a large repository of samples from 9/11 first responder fire fighters, and non-exposed fire fighters as a control. We will leverage this unique sample repository and our newly developed methodology to study over time blood stem cells of individuals who have donate samples to this repository. Our study will be instrumental to improve diagnostic assessment, including at blood the stem cell level, and this may help to improve treatment selection focused on the true root of the disease. In addition, our study may be helpful for the development of treatment strategies for the prevention of leukemia in the future.

Weixing Zhao, Ph.D.

Funded by Hooters of America, LLC

According to estimates from the International Agency for Research on Cancer, worldwide, there were 18.1 million new cancer cases diagnosed with 9.6 million deaths in 2018. In other words, one in 5 men and one in 6 women experience cancer during their lifetime, and one in 8 men and one in 11 women die from the disease. As such, there is an urgent need for finding better treatments to reduce cancer-associated death. BRCA1 and BRCA2 are two genes that, when mutated, can cause cancer. Studies by many research groups have revealed critical roles of BRCA1 and BRCA2 in protecting our genetic material from damage caused by sunlight, radiation, and other environmental exposures. While BRCA mutations have been linked to a greatly increased risk of developing cancer, we do not yet fully understand the biological process of DNA repair mediated by the BRCA genes. This poses a challenge for patient counseling, determining prevention strategies, and the formulation of treatment plans when disease strikes. Here, we describe a research project to study BRCA1 and BRCA2 designed to fill this knowledge gap. The information and tools from our work will help explain why BRCA mutations cause disease and help formulate treatment regimens that are more effective than current ones.

Sidharth Puram, M.D., Ph.D.

Head and neck tumors are composed of cells that are not all the same, but instead have different functions, much like bees in a hive. While some cells act like drone bees that are primarily responsible for expanding and growing the colony (or in this case, tumor), others are responsible for directing and orchestrating the tumor like a queen bee. Still other cells mimic worker bees who travel outside the hive and are responsible for the spreading the tumor to new locations. We are interested in these worker bees of head and neck cancers and understanding what triggers them to exit the hive. In particular, we are trying to identify the specific genes that serve as markers of the worker bees, in order to determine if they are present in tumors and whether they can help to predict when a cancer may spread. We are also trying to understand the specific genes that allow these worker bees to perform their function. Much like a specific wing shape or other adaptations worker bees have in nature, we are curious about whether these cells have specific cellular machinery they use to spread beyond the tumor. Together, these studies could help us develop new ways of identifying patients at risk for their cancer spreading as well as new treatments to prevent the spread of cancer all together.

Devon Lawson, Ph.D.

The overarching goal of research in my laboratory is to understand how cancer cells metastasize and spread to vital organs in the body, such as the lung, liver, bone and brain. In breast cancer patients, metastasis leads to death in over 40,000 women in the U.S. each year. The possibility of progression to stage IV, metastatic disease is a constant source of fear and anxiety, since 30% of patients eventually progress to metastasis and survival for these patients is very poor (<3 years). Despite its prevalence, metastasis is an incredibly complex biological process that is very challenging to study due to the limited availability of authentic model systems. My laboratory has developed an innovative new approach to study metastasis in high resolution, using cutting-edge new single-cell technologies to study how individual cancer cells spread in human patient tumor models of breast cancer. Using our approach, we have found that cancer cells use a specialized form of cellular metabolism in order to spread. In our proposed study, we will investigate why and how this form of metabolism promotes cancer cell spread, and we will explore the effectiveness of using metabolic inhibitors to prevent metastasis and fatality in cancer patients.

Pratiti Bandopadhayay, M.D., Ph.D.

Funded by the Dick Vitale Pediatric Cancer Research Fund

Diffuse Intrinsic Pontine Gliomas (DIPGs) are heartbreakingly aggressive tumors of childhood for which no curative treatments currently exist. Our research is focusing on a gene called PPM1D which is commonly mutated in DIPGs. We are studying how these mutations cause the tumors to grow and are trying to find ways in which we can target them in new treatments for children with DIPG.

Keriann Backus, Ph.D.

Funded by the Constellation Gold Network Distributors

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Many NSCLCs are caused by exposure to carcinogens, such as cigarette smoke, which cause changes to a cell’s DNA. These genetic changes can be detected by DNA sequencing methods. Next generation sequencing of tumors can provide clinicians, patients, and researchers with essential knowledge about the genes and proteins that cause and contribute to disease. Unfortunately, most human proteins (>95%) remain undrugged or inaccessible to labeling by FDA approved small molecules. Consequently, most cancer-associated proteins identified by DNA sequencing cannot be drugged. Therefore, we need new methods to identify druggable pockets in cancer-causing proteins. Our research develops such technology. In this study, we will develop a new approach to translate genetic changes into therapies. Our first step is to identify drug vulnerabilities that are specific to tumors. We will achieve this goal by combining next generation sequencing with new proteomics methods developed by our group. Next, we will synthesize drug-like molecules that can specifically label these tumor-associated proteins. Finally, we will determine how the protein targets of our compounds cause or contribute to cancer. Long-term, our studies will help guide the development of new precision therapies that will have fewer side effects and improved patient outcomes.

Ludmil Alexandrov, Ph.D.

Abeloff V Scholar* (Tied for Top Rank)

The term “metastasis” describes the spread of cancer cells from their original location in the body to nearby or distant organs. Almost 90% of all cancer deaths are because of metastasis. Unfortunately, this estimate has not changed in the last 50 years and our understanding of metastasis is limited. In order to effectively treat metastasis, we need to first understand them.
Both cancers and their metastasis contain mutations in their DNA. Using our advanced algorithms, we can utilize these mutations to generate a tree that shows the evolution of a cancer in an individual cancer patient. On this tree, we can map the most important changes that can be used by doctors for making treatment decisions. In addition to using individual mutations, we can also use the patterns of all mutations in a cancer patient to pinpoint the processes that were active during evolution of the cancer. Some of these processes can be used as clocks to time the important changes found on the tree.
Overall, we will create a high-definition timeline of the molecular events in the metastatic cancer of each individual cancer patient. The project will examine almost 2,000 cancer patients and increase our understanding of the events needed to transform a cancer to a metastasis. This knowledge is an essential step in providing patients with metastatic cancer with an informed and optimal cancer treatment.

Linda Sutton, M.D.

Funded by the Victory Ride to Cure Cancer

Clinical trials offer a path to cure for cancer patients by testing methods to prevent, find or treat many types of illness. Yet, patient access to clinical trials varies; rural areas have limited health care services. Duke University has a wealth of clinical trials for patients with cancer. The goal of this effort is to increase the clinical trials available from Duke to the community. The clinical trials will focus on specific ethnic groups in specific locations. Two types of clinical trials will be the focus: Uncommon cancers– such as blood-based cancers, or cancers that have different effects on specific races – such as prostate.

Duke doctors with special knowledge in Prostate Cancer and blood cancers will go to specific clinics. The Duke doctors will talk with doctors and nurses in the community about patient cases. We will test to see if rural clinics can use central storage for test results from tumors. Central storage will let us match test results from tumors to available clinical trials.

Our team wants to include patients in our effort to improve knowledge about clinical trials. We want to help make them aware that clinical trials are available. A committee that includes patients will help guide the creation of educational tools for patients.

James Larner, M.D. & David Brautigan, Ph.D.

Funded by the V Foundation’s Virginia Vine event

Prostate cancer afflicts one in seven men and is their second leading cause of death, justifying development of more effective therapies. Prostate cancer depends on testosterone binding to and activating the androgen receptor (AR), which in turn promotes the growth of prostate cancer. Current therapies for prostate cancer are aimed at reducing AR activity, either by blocking the production of testosterone or through agents which compete with testosterone for binding to the AR. Our approach is depleting cancer cells of the AR protein by promoting its degradation. We will accomplish this by manipulating the pathways (either genetically or with drugs) which control protein degradation. Our preliminary data show that we can promote degradation of the AR in cells in test tubes. In this proposal we will test if we can promote AR degradation in mouse models of prostate cancer.

Meenakshi Hegde, M.D.

Funded by the Dick Vitale Pediatric Cancer Research Fund

Sarcomas are cancers of connective tissues in the human body. It affects children and teenagers more than adults. Cancers that spread to other parts of the body are difficult to treat and are not often curable. A new treatment approach called immunotherapy uses the body’s own immune system to fight cancer. Our approach uses immune cells of the body, namely T cells, to find and kill tumor cells after introducing an artificial molecule called chimeric antigen receptor (CAR). These CAR-enhanced T cells developed in our laboratory recognize a protein on the surface of the cancer cell, namely HER2. Patients with advanced sarcoma received these HER2-specific CAR T cells in our ongoing clinical trial. The CAR T cells did not cause severe adverse reactions in any of the treated patients. More than half of the 10 patients who received the cell treatment benefited from it, with 2 patients achieving tumor elimination and 4 others achieving cancer stabilization. We will now test if larger dose of T cells can be tolerated or increase the chances of benefit. We will also study immune responses in these patients to identify mechanisms, if any, that can lead to improved treatments. Finally, we will evaluate a new molecule that can help CAR T cells overcome tumor signals that turns them off. The insights gained from this study will help design and develop targeted treatments for sarcoma.