Research related to breast, pancreatic and lung cancers are among the 11 projects that will benefit from $2.55 million in new grants announced by Siteman Cancer Center. The grants, given through the Siteman Investment Program, are meant to support and accelerate the pace of innovation in cancer research.
The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at the Foundation for Barnes-Jewish Hospital; Swim Across America – St. Louis, the Fashion Footwear Association of New York; the National Cancer Institute; and the Barnard Trust.
The research projects are described below.
Title: Angiogenic mechanisms enhancing anti-tumor immunity
Principal investigator: Kyunghee Choi, PhD, a professor of pathology and immunology at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To develop a drug to block abnormal tumor blood-vessel formation in order to enhance cancer immunotherapy treatment
Description: Tumor blood vessels are known to be abnormal, dilated, leaky and tortuous and to have slow blood flow. Recent studies have suggested that normalizing such abnormal blood vessels might enhance cancer immunotherapy. As such, there is great interest in the combined cancer blood-vessel therapy and immunotherapy. However, current major blood-vessel drugs, mainly targeting the vascular endothelial growth factor (VEGF) or VEGF receptor 2 (VEGFR2), have proven to be suboptimal, largely due to limited effectiveness, serious side effects and high cost. As such, discovering new targets may improve the current limitations of cancer blood-vessel therapy. We identified MYCT1 to be such a molecule. MYCT1 was specifically required for tumor blood-vessel formation. Combined treatment using a strategy to knock down Myct1 expression with immunotherapy was highly effective in inhibiting tumor growth. Based on these exciting preliminary data, we will develop a drug against MYCT1 to block its function and to assess its efficacy in cancer treatment together with immunotherapy.
Title: Functional characterization of an uncharacterized cytokine, Gm525, as a potential target for cancer therapies
Principal investigator: Takeshi Egawa, MD, PhD, an associate professor of pathology and immunology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand and test a recently discovered phenomenon in which cancer cells promote their own growth by releasing a molecule and develop tools to inhibit this cancer promoting mechanism
Description: We do not completely understand how cancer arises from normal cells. While errors in copying the genome during cells division and subsequent changes in gene expression are major drivers for cancer development, it is predicted there are additional causes that increase the risk of cancers or make cancer resistant to therapies. In our recent studies using mouse models of leukemia, a cancer derived from blood cells, we have found an intriguing phenomenon, in which cancer cells produce a soluble factor, like a hormone, that may promote their own growth. In this project, we will perform additional studies to test whether this is a common cancer-promoting mechanism shared by various cell types and also to develop tools to suppress cancers by inhibiting this mechanism. We expect this study will lead to the development of a new therapy that is distinct from conventional methods.
Title: Role of DKK1 in breast cancer progression and immune suppression
Principal investigator: Roberta Faccio, PhD, an associate professor of orthopaedic surgery at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To investigate the effects of neutralizing a factor produced by bone cells, in conjunction with chemotherapy and/or immune therapy, to increase the efficacy of these cancer therapies in breast cancer
Description: Although the majority of breast cancer cases are diagnosed early, approximately 10-20 percent of patients recur within 10 years. Unfortunately, once the tumor cells spread to various organs, treatment options are limited. Immune therapy, aimed at increasing the tumor-killing power of the patient’s immune cells, has transformed cancer treatments in recent years, giving hope to patients previously considered terminal. However, the response rate to immune therapy on breast cancer is low. We recently discovered that a factor produced by the bone cells, DKK1, is increased during tumor progression and creates an “immune suppressive environment” where the very cells that could destroy the tumor (T cells and NK cells) are unresponsive, allowing tumor cells to grow undisturbed. DKK1 correlates with poor outcome in breast cancer. Thus, we will investigate the effects of DKK1 neutralization, in conjunction with chemotherapy and/or immune therapy, to bolster anti-tumor immune responses and kill resistant tumor cells.
Title: Developing strategies to prevent and treat chemotherapy-induced neuropathy
Principal investigator: Stefanie Geisler, MD, an assistant professor of neurology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To investigate different therapeutic strategies that block a mechanism that leads to nerve fiber damage during chemotherapy treatment and ultimately prevent chemotherapy-induced neuropathy
Description: Many commonly used chemotherapy regimens have peripheral neuropathy as a side effect. Chemotherapy-induced neuropathy is characterized by numbness, tingling, burning pain, imbalance and weakness in hands and feet. In contrast to other side effects, the neuropathy can last long after chemotherapy has ended and cause permanent disability. There are no treatments that can prevent chemotherapy-induced neuropathy. Others and we have identified mechanisms that lead to nerve fiber damage during chemotherapy. We discovered that different chemotherapeutics activate a protein called SARM1, which rapidly breaks down the essential metabolite (fuel) NAD+, thereby leading to metabolic collapse and nerve fiber breakdown. Here, we will investigate different therapeutic strategies that block this final common axon destruction pathway in an animal model. These are important steps toward translating our findings to the clinic, where such a therapy could benefit millions of cancer patients.
Title: Modeling anti-PDL1 response and resistance in naturally occurring canine cancer
Principal investigators: Obi Griffith, PhD, an associate professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center, and Jeffrey Bryan, DVM, PhD, a professor of oncology at the University of Missouri
Goal: To develop new methods for measuring immune therapy response and resistance in companion dogs and ultimately to create a powerful new system for understanding and improving immune therapies in both humans and companion animals
Description: Immune therapies show promise in treating deadly cancers, but failures are not predictable and responses can be brief. Companion dogs naturally develop many of the same cancers as people do for many of the same reasons and in a similar immune environment. This is an ideal setting to understand why immune therapies succeed or fail in cancer patients. However, many of the necessary tools and computational approaches used to study the immune system in humans and mice are underdeveloped for dogs. We will develop new methods for measuring immune therapy response and resistance specifically for use in dogs. This will help create a powerful new system for understanding and improving immune therapies in both humans and companion animals. In this study, by testing canine (dog) melanoma with widely used immune therapies from human medicine, we hope to better understand why some patients respond and others fail and why resistance develops.
Title: Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome
Principal investigator: Andrea Hagemann, MD, an associate professor of obstetrics and gynecology at Washington University School of Medicine and research member of Siteman Cancer Center
Goal: To create a standard toolkit for cancer providers to utilize for cancer patients with inherited disease-causing genetic mutations and their family members, to educate on the importance of undergoing genetic testing
Description: Currently, cancer patients with inherited disease-causing mutations such as BRCA1 or BRCA2 bear the burden of educating their family members about the need to undergo genetic testing. There are currently no standard methods for cancer providers to help their patients with this. Once family members are tested, they may not have easy access to prevention strategies. This project tests a toolkit to be used by providers, patients with mutations (probands) and family members, containing educational materials, testing options and counseling and treatment resources. If this toolkit is successful, then further studies and large-scale implementation could allow thousands of people each year to learn of their cancer risk and undergo early screening or treatments, preventing many cancers altogether.
Title: Development of Novel ERK Inhibitor-Based Therapeutic Combinations In Pancreatic Cancer Based On Proteo-Transcriptomic Analyses
Principal investigator: Kian Lim, MD, PhD, an assistant professor of medicine at Washington University School of Medicine and research member of Siteman Cancer Center
Goal: To develop new therapeutic strategies that can more effectively target the activated signaling pathway in pancreatic cancer and ultimately improve patient outcomes
Description: Effective treatment for patients with pancreatic cancer is an urgent, unmet medical need. Targeting the cancer-driving events within pancreatic cancer cells bears the highest chance of therapeutic breakthrough. Pancreatic cancer is characterized by activation of a signaling pathway called the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is analogous to a “gas pedal” in a car, and in normal cells is tightly controlled by many “braking” mechanisms. In pancreatic cancer, this gas pedal is constantly engaged due to a near universal mutation of the KRAS gene. For decades, attempts to slow down the MAPK pathway has not been successful, and all evidence point towards ERK, a critical signaling node within the MAPK pathway, that is very difficult to suppress. Using patient samples and cell lines studies we have now uncovered a novel mechanism by which cancer cells can resist ERK inhibition. Our proposal focuses on developing novel combinatorial therapeutic strategies that can more effectively curb ERK to improve patient outcome.
Title: Recurrent long, non-coding RNA gene fusions across solid tumors
Principal investigator: Christopher Maher, PhD, an associate professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand how a fusion gene causes tumor growth in 11 different cancer types, and ultimately to identify a targeted therapy to inhibit the fusion genes and ultimately prevent cancer progression
Description: Our lab has extensive experience identifying regions of the human genome that are “rearranged” as a tumor develops. This process results in two completely independent genes becoming “fused” together (referred to as a “fusion gene”). Since fusion genes are specific to tumor cells they represent ideal diagnostic and prognostic markers. Novel therapies targeting the fusion gene are also more effective by killing cancer cells without affecting normal cells. Therefore, this study focuses on our recently discovered novel fusion gene that was observed in patients with 11 different cancer types. This study will focus on understanding how the fusion gene promotes tumor progression. This research is critical to achieve our longer-term goal to “drug” this fusion gene using existing FDA approved drugs. This will be of broad impact given the large patient population that has the fusion gene.
Title: Implementing multilevel smoking cessation interventions to reduce rural cancer disparity
Principal investigators: Li-Shiun Chen, MD, an associate professor of psychiatry at Washington University School of Medicine and research member of Siteman Cancer Center, and Aimee James, PhD, a professor of surgery at Washington University School of Medicine and research member of Siteman Cancer Center
Goal: To reduce the high smoking prevalence in rural communities with a multi-level strategy to help patients quit smoking and reduce health disparity in rural communities
Description: Smoking is a leading modifiable risk factor for disability and death in patients within rural communities. Rural southern Illinois, part of the Siteman Cancer Center catchment area, has high prevalence of smoking and lung cancer. There is a tremendous need for smoking cessation treatment in rural clinics, which often must contend with long travel distances for care, lack of training and infrequent service utilization. This study will test the effect of a low-burden, multi-level strategy in rural health clinics to help these patients quit smoking. This innovative research will leverage technology to assess smoking and facilitate consistent delivery of evidence-based cessation treatment at low burden and low cost to the rural health clinics. Our study will set the foundation for a future successful implementation trial (R01 grant) of a multi-level strategy to reduce smoking in rural communities. This project is significant because these implementation strategies can be easily disseminated and have the potential to significantly reduce smoking and associated disability and death in patients in rural communities.
Title: Targeting the Nonsense-mediated RNA decay (NMD) pathway in cancer with aberrant splicing
Principal investigators: Zhongsheng You, PhD, an associate professor of cell biology and physiology, and Matthew Walter, MD, a professor of medicine, both at Washington University School of Medicine, and both research members of Siteman Cancer Center
Goal: To test if targeting a particular RNA degradation pathway in cells with spliceosome gene mutations (responsible for multiple types of cancer) is a viable strategy to treat cancer
Description: RNA splicing is an important process in cells that cuts and stitches RNA segments together to generate mature RNA required for normal cell function. Many blood cancers and solid tumors are caused by mutations in genes that regulate RNA splicing (i.e., spliceosome genes). Cells with these mutations produce many abnormal RNAs, including nonsense messenger RNAs which can generate abnormal proteins that cause deleterious effects, including cell death. Because nonsense messenger RNAs are normally cleared up by the nonsense-mediated mRNA decay (NMD) pathway in cells, we hypothesize that inhibiting the NMD pathway can kill cancer cells with spliceosome gene mutations. Building on our preliminary results and the complementary expertise and strengths of two labs, we propose in this project a series of innovative studies to test the idea that targeting NMD is a viable therapeutic strategy for cancer treatment.
Title: Phase I trial of best-in-class JAK inhibitor, baricitinib, as prophylaxis of Graft versus Host disease (GvHD) in patients undergoing allogeneic hematopoietic cell transplantation for hematologic malignancies
Principal investigator: Mark Schroeder, MD, an associate professor of medicine at Washington University School of Medicine and research member of Siteman Cancer Center
Goal: To explore whether blood cancer patients who receive blood or marrow transplants experience less GvHD when given baricitinib
Description: Blood cancers remain a significant public health problem, accounting for about 10 percent of new cancer diagnoses. Patients can often be cured by blood or marrow transplants. However, in about 50 percent of cases the donated immune system sometimes attacks the patient’s skin, intestines and liver. This very debilitating and sometimes fatal condition (about 25 percent of victims) is known as GvHD. In our first-in-human phase I clinical trial we will explore whether blood cancer patients who receive blood or marrow transplants experience less GvHD when given baricitinib. In studies in mice, baricitinib was shown to prevent GvHD while allowing the immune cells to retain their ability to attack the cancer cells. Our hope is that this simple approach will improve transplant outcomes by decreasing a major side effect after transplant, result in cures of blood, bone marrow, and lymph node cancers and provide a significant step forward in the field.