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The University of Cincinnati Cancer Center Pilot Project Award Program is dedicated to advancing cancer research by providing pilot funding to our faculty investigators. The $50,000 awards are granted twice annually. The program is supported by generous contributions from the following partners: The Bergman Family Research Fund, Brandon C. Gromada Head and Neck Cancer Research Pilot Grant, GIVEHOPE Pancreatic Cancer Research Grant, BSI Engineering Pancreatic Cancer Research Grant, Lyle and Gretchen Shaw Cancer Research Fund, Marlene Harris-Ride Cincinnati Cancer Pilot Program, Steven Goldman Memorial Pancreatic Cancer Research Grant, William Wong Family Cancer Research Fund, Jeff and Gail Forlenza Fund, and Mischell Family Prostate Cancer Research Pilot Grant.
The goals of the Pilot Project Award Program are to:
Head and neck squamous cell carcinoma (HNSCC) is a significant global health concern, ranking as the sixth most prevalent cancer worldwide. Unfortunately, its 5-year survival rate is only 65%. The current treatment approach involves a combination of surgery, conventional photon X-ray radiation therapy (RT), and sometimes chemotherapy. Recently, proton therapy has emerged as an exciting alternative for treating head and neck cancer.
“Unlike X-ray therapy, proton therapy can more precisely target tumors while sparing surrounding healthy tissues, potentially reducing side effects,” explained Dr. Conforti, a Professor in the Department of Internal Medicine at the University of Cincinnati’s College of Medicine. “However, there is still limited information about the biological and immunological benefits of proton therapy compared to traditional photon treatment. We know that cancer cells use various strategies to evade the immune system, which is designed to destroy them. One such strategy involves the production of small extracellular vesicles called exosomes, which can suppress immune cells both locally and throughout the body. Our research aims to understand how proton radiation impacts exosome production, ultimately influencing the body's anti-tumor immune response.”
With an overall laboratory focus on understanding why the immune system often fails to attack and eliminate cancer cells, Dr. Conforti and her team specifically investigate the strategies cancer cells use to evade the immune system and how these strategies affect immune cell function. Their expertise lies in their ability to study immune cells in controlled environments where they can observe how they respond to cancer cells and attempt to eliminate them. By understanding these processes, she and her team hope to uncover new ways to enhance the immune system’s ability to fight cancer, which could lead to the development of innovative therapies that improve the effectiveness of cancer treatments and ultimately save lives.
Dr. Conforti will be utilizing this award to support the Effect of Proton Radiation on Exosome Production in Head and Neck Cancer project she is leading. The team’s work will shed light on how proton radiation influences the production of exosomes, which play a role in modulating the immune response against cancer. This knowledge could pave the way for novel therapeutic strategies that leverage the body's immune system to better fight cancer.
“The findings from our studies will provide new insights into the differential effects of proton and photon radiation on tumors,” she shared. “By understanding these differences, we can enhance the effectiveness of proton therapy in treating head and neck cancer. This research could lead to more precise and personalized treatment plans, improved survival rates, and reduced side effects for patients.”
While expressing her gratitude for this award, Dr. Conforti explained just how impactful it is to her team’s work as well as to the future of cancer therapy and prevention.
“Receiving this award provides crucial funding that enables us to conduct pilot studies that will inform us of new processes involved in cancer,” she shared. “These initial investigations are necessary for developing and refining hypotheses. On a personal and professional level, this grant represents a significant milestone. It allows us to pursue innovative and untested hypotheses that could lead to groundbreaking discoveries in cancer research. The ability to explore these new ideas without the constraints of larger, more rigidly defined grants fosters creativity and potential high-impact results.”
“In the long term, the insights gained from these pilot studies could further our understanding of cancer biology, leading to more effective treatments and improved patient outcomes,” she continued. “This support is not just an investment in our research, but an investment in the future of cancer therapy and prevention. Without it, we would miss the opportunity to explore these critical early-stage ideas that have the potential to transform the field.”
Dr. Conforti also took a moment to share how her Cancer Center membership has helped develop and advance her research.
“The Cancer Center has provided numerous opportunities for collaboration and information sharing through research seminars, retreats, and symposiums, at which I can engage with colleagues and exchange ideas regularly,” she said. “Despite being a relatively small community, the Cancer Center is highly diverse, which fosters collaborations across various disciplines, including basic science researchers, oncologists, radiation oncologists, and surgeons.”
“This diversity has expanded the breadth of our collaborative efforts,” she mentioned. “Additionally, the Cancer Center offers a well-organized system for procuring specimens from the clinic, which is crucial for our translational research. Access to these clinical specimens ensures that our research is directly applicable to patient care and can swiftly translate into clinical advancements.”
The bioaccumulation of PFAS compounds in humans has well-documented harmful effects on a myriad of health outcomes, including the risk of cancer. Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a large group of synthetic chemicals that are used in many consumer, commercial, and industrial products.
PFAS are persistent in the environment and break down very slowly over time. They can migrate into the soil, water, and air during production and use, and are found in the blood of people and animals all over the world. Recent studies have linked PFAS exposure to harmful health effects in humans, including thyroid disease, immune system disruption, risk of cancer, and low birth weight.
“There are few studies that have investigated associations between pre-diagnostic serum levels of PFAS and medical diagnoses of cancer using a longitudinal design and extensive cancer risk factor data,” explained Dr. Pinney, Director of the Center for Environmental Genetics and a Professor in the Department of Environmental and Public Health Sciences at the University of Cincinnati’s College of Medicine. “We propose to use the data and biospecimens of the Fernald Community Cohort (FCC) to examine PFAS exposure and cancer incidence in persons in the greater Cincinnati area.”
The Fernald Community Cohort consists of 9,782 people who participated in the Fernald Medical Monitoring Program (FMMP) from 1990 to 2008. The FMMP was an eighteen-year medical surveillance program for community residents living near the former US Department of Energy uranium processing site at Fernald, Ohio.
“We are uniquely positioned to have access to longitudinal historical medical records, cancer diagnosis validation, cancer histology, questionnaire data and pre-diagnostic archived biofluids of persons in the cohort,” said Dr. Pinney. “We propose to test the hypothesis that PFAS exposure is associated with incidence of breast, prostate, renal and bladder cancer.”
Dr. Pinney will be utilizing this award to support the Association Between PFAS Exposure and Cancer Incidence project she is leading. The focus of the project is to determine if there is an association between levels of PFAS in serum and later diagnosis of incident cancer.
“It takes a long time for epidemiological research to have an impact, but I have seen my research on the health effects of PFAS influence the need for an EPA to declare PFAS as hazardous substances and issue a national drinking water standard,” she explained. “If we should find a relationship between PFAS and one or more cancers, and also discover a difference in DNA methylation between those with higher PFAS exposure and those with less exposure, we will better understand how PFAS perturb various physiological processes.”
While expressing the importance this funding holds for the project, Dr. Pinney also shared how influential her Cancer Center membership has been for her work.
“The funds in the pilot grant will allow us to produce additional preliminary data for the grant and preliminary data that are more scientifically robust,” she said. “In the first submission of the grant, we used PFAS measurements made for other studies to try to show a relationship between PFAS exposure and cancer. With these additional funds, we can use a formal sampling procedure to select additional samples for both cases and controls.”
“In addition to this funding, my Cancer Center membership has given me a platform to present my research ideas and receive feedback from colleagues with similar research interests,” Dr. Pinney shared. “This combination will certainly allow us to greatly enhance the preliminary data.”
The global surge of obesity has reached epidemic proportions, and a clear link between hepatosteatosis and hepatocellular carcinoma (HCC), i.e. liver cancer, development has been established. Hepatosteatosis, also known as fatty liver disease, is a condition where too much fat accumulates in the liver, and it occurs when the liver can't metabolize or secrete fat as fast as it's delivered.
Research proposes various mechanisms explaining how obesity elevates cancer risk, notably through dysregulating the mechanistic target of rapamycin (mTOR), critical for growth, homeostasis, and nutrient management. This dysregulation, alongside disturbed nutrient intake, raises several cancer risks, particularly hepatocellular carcinoma. The precise impact of obesity and mTOR on cancer, especially HCC, is unclear.
Preliminary data shows that small extracellular vesicles (sEVs) with specific RNA cargos play a key role in mTOR-driven liver cancer, or hepatocellular carcinoma. When mTOR is activated in the liver, it disrupts processes like protein synthesis, promoting liver cancer. Additionally, macrophages and Kupffer cells release inflammatory cytokines that worsen the cancer, though the impact of immune responses in mTOR-driven liver cancer is not well understood.
Dr. Nakamura, an Associate Professor in the Department of Pediatrics at the University of Cincinnati’s College of Medicine, will use this award to support the Exploring the Pathogenic Bridge: Obesity, mTOR Dysregulation, and Hepatocellular Carcinoma via Small Extracellular Vesicles project he is leading. This project aims to explore the role of sEVs, particularly liver-derived sEVs, in mTOR-driven liver cancer using genetic and molecular methods.
The blood-brain barrier is a natural defense system that separates the brain from circulating blood, which makes it extremely difficult for many drugs to reach brain tumors. Furthermore, brain tumors can manipulate the blood-brain barrier (BBB) to create a protective niche and effectively hide from immune cells and therapies specifically designed to target them.
“This grant will boost our ongoing endeavor to develop a human-relevant model of brain tumors designed to accelerate the development of innovative therapeutic strategies, such as gene therapy and immunotherapy, for aggressive forms of brain cancer,” explained Dr. Barrile, an Assistant Professor in the Department of Biomedical Engineering at the University of Cincinnati’s College of Engineering and Applied Science.
Dr. Barrile will be utilizing this award to support the Enhancing Therapeutic Delivery of Adenoviral Particles and Immune Cells in a Microfluidic Brain Tumor Model through Focused Ultrasound project he is leading. This project proposes a pioneering approach to address the challenges in treating aggressive brain tumors by tackling the formidable obstacle of the blood-brain barrier (BBB). It centers on utilizing low-intensity focused ultrasound (FUS) to transiently open the BBB, facilitating targeted drug delivery to brain tumors. The primary objective involves validating a human-relevant brain tumor-on-a-chip model for translational studies on FUS-mediated drug delivery.
Brain tumor-on-a-chip models are 3D biometric models that can help researchers study brain tumors and their interactions with the brain microenvironment. These models can be used to study cell behavior, screen drugs, and test therapies. They can also assist researchers in developing personalized treatment strategies that could improve patient survival rates and efficacy.
“The successful validation and application of our tumor-on-a-chip platform for studying focused ultrasound-mediated drug delivery in brain tumors can pave the way for personalized and targeted therapeutic strategies,” Dr. Barrile shared. “This project will support our efforts toward generating new tools and methods for testing novel targeted therapies against brain tumors.”
“In this project, we will work towards establishing a model that includes primary or metastatic cancer cells and human blood-brain barrier cells, recapitulating key tissue structures and functions of the perivascular niche of brain tumors using patient-derived cells,” he explained.
While expressing his appreciation for this funding, Dr. Barrile also took the time to note how his Cancer Center membership helped to develop and advance the research he and his team are doing.
“Cancer Center membership has been key in advancing my research by fostering a collaborative and multidisciplinary environment,” he said. “The Cancer Center promotes frequent interactions with both scientists and physicians, which has enabled me to integrate diverse expertise and perspectives into my work. Additionally, access to the Cancer Center's state-of-the-art facilities and resources has significantly accelerated the pace of our research endeavor.”
Acute myeloid leukemias (AML) are especially dependent on epigenetic regulators – proteins and enzymes that modify the expression of genes without altering the DNA sequence – to maintain tumorigenicity, or the cancerous state of the cells. AML cells rapidly adapt to chemotherapeutic interventions by altering their state and morphing into novel cell identities with inherent properties that resist the therapy.
“Acute myeloid leukemia is particularly challenging to treat because it is driven by an expansion of partially differentiated blood progenitor cells,” explained Dr. Volk, an Assistant Professor of Experimental Hematology and Cancer Biology at Cincinnati Children’s. “These cells are highly adaptable to stresses caused by cytotoxic chemotherapy, but they are susceptible to pro-differentiation stimuli. The focus of this pilot is to develop first-in-class degrader molecules that can remove the primary barrier to differentiation in leukemia by targeting the chromatin assembly complex.”
Dr. Volk will be utilizing this award to support the Discovery of Novel CAF1 Degraders by DNA-Encoded Library project he is leading. The primary goal of this pilot project is to use the team’s purified protein as a bait substrate for capturing potential binding molecules that can then pursue as lead compounds for degrader molecule development.
The team discovered that the Chromatin Assembly Factor 1 (CAF1) complex is a master epigenetic regulator of cell fate in AML as part of its canonical nucleosome assembly role during replication. CAF1 is upregulated in AML, and this disease is addicted to high levels of CAF1. Even partial repression of CAF1 is sufficient to drive differentiation and maturation to a non-leukemic state in every AML line/sample tested.
“Conventional chemotherapy kills cancer cells but also acts as an evolutionary pressure on the tumor to adapt, which leads to resistance,” explained Dr. Volk. “Differentiation therapies circumvent this process by pushing the leukemias along their originally intended maturation path. The only current differentiation therapy available works for one specific subtype of AML. Targeted degradation of the chromatin assembly complex drives differentiation universally in leukemias.”
Partial repression of CAF1 has no discernable phenotype in any healthy tissue. Unfortunately, there are no compounds available that can target the CAF1 complex for degradation for use as a novel AML therapeutic. The team, however, generated high-purity CAF1 complex protein as part of a previous project to solve the CryoEM structure for CAF1.
“Manipulation of the chromatin assembly complex as a cancer therapy is an exciting concept, as all components are almost universally upregulated in cancer,” he said. “Additionally, using DNA encoded small molecule libraries as a means to identify novel compounds is a powerful new technology that we are bringing to the Cancer Center.”
While expressing his gratitude for this award, Dr. Volk also took the time to note how collaboration through his membership with the Cancer Center helped develop and advance the research he and his team are doing.
“This award funds our efforts to acquire and utilize the DNA encoded library to determine high-confidence molecular warheads that can degrade the chromatin assembly complex,” Dr. Volk shared. “Without this key and generous funding, we would not have the resources to devote to this project.”
“Furthermore, I always remind my trainees that science does not occur in a bubble,” he remarked. “Our membership with the Cancer Center gives us crucial access to collaborators as well as feedback from expert researchers and clinicians across the entire field. These interactions keep us out of the weeds and sharpen our science so that we can have the highest impact possible.”
Recently, colorectal screening guidelines have changed from 50 years to 45 years of age. However, the incidence rate in the United States, and other western populations, in patients younger than 45 years of age continues to increase.
“The incidence is notably higher in the Cancer Center’s catchment area and neighboring states in comparison to other parts of the United States,” explained Dr. Kharofa, an Associate Professor in the Department of Radiation Oncology at the University of Cincinnati’s College of Medicine. “This is very evident in our clinics at the Cancer Center. It is no longer uncommon to see young patients with colorectal cancer. Given these alarming trends, our group has focused on evaluating potential environmental contributors to this problem. We are specifically evaluating bacterial species in the gut microbiome that may be associated with young onset colorectal cancer.”
Dr. Kharofa will be using this award to support the Sulfidogenic Bacteria and the Risk of Young Onset Rectal Cancer project he is leading. This project will leverage his team’s experience using publicly available metagenomic data and institutional metagenomic samples to elucidate associations of sulfur metabolizing genes with colorectal cancer overall, as a function of age, and specifically in patients with rectal cancer. These studies will, then, lay the foundation for extramural applications targeting sulfur metabolizing species in rectal cancer.
“In our previous fecal metagenomic metanalysis, we examined the relative abundance of all species differentially enriched in young onset colorectal cancer compared to controls and older patients with Colorectal cancer,” Dr. Kharofa shared. “Notably, we observed enrichment of Bilophilia wadsworthia and Alistipes putredinis in young onset colorectal cancer relative to both older colorectal cancer patients and healthy controls.”
Dr. Kharofa explained that this finding was intriguing due to the role they play in sulfur metabolism and production of hydrogen sulfide, which had not been previously demonstrated in young onset colorectal cancer.
“Hydrogen sulfide has been observed to have carcinogenic potential,” said Dr. Kharofa. “We hypothesize that sulfur metabolizing bacteria act as mediators of colorectal cancer carcinogenesis and contribute to the increase in early onset rectal through dietary metabolism of sulfur to hydrogen sulfide.”
With this grant, Dr. Kharofa and his team will be studying the association of sulfur metabolizing genes across bacteria in the microbiome and their association with colorectal cancer. They will also specifically evaluate sulfur metabolizing genes and species specifically in patients with rectal cancer.
“This grant will provide crucial preliminary data to elucidate how dietary factors may interact with gut bacteria to produce carcinogenic byproducts,” explained Dr. Kharofa. “This may in turn explain the rising incidence of colorectal cancer in younger populations.”
This work is an ongoing collaboration of researchers at the Cancer Center with members from the University of Cincinnati and Cincinnati Children’s. As part of this effort, the team will be collecting stool samples from the local community for patients diagnosed with colorectal cancer for comprehensive analysis in the Microbial Metagenomics Analysis Center at Cincinnati Children’s.
Joan Garrett, PhD Member, Experimental Therapeutics
According to the American Association for Cancer Research, an estimated 152,810 people in the United States are expected to be diagnosed with these cancers and 53,010 are expected to die of colorectal cancer. Approximately 40% of colorectal cancer patients contain a KRAS mutation, which makes the tumors more aggressive. A KRAS mutation in colorectal cancer (CRC) occurs when the KRAS oncogene mutates, causing cells to grow too much and potentially leading to cancer. Additionally, there is a significant statistical co-occurrence of HER3 and KRAS mutations in CRC patients.
“There are ongoing clinical trials with KRAS inhibitors, and KRAS inhibitors have been FDA approved in lung cancer,” explained Dr. Garrett, an Associate Professor in the Division of Pharmaceutical Sciences at the University of Cincinnati’s James L. Winkle College of Pharmacy. “Co-targeting KRAS and the HER family is a new avenue of research in KRAS mutant CRC with the goal of better outcomes for patients.”
Dr. Garrett will be using this award to support the Probing the Role of Mutant KRAS and Co-Mutated HER3 in Targeted Therapy Response in Colorectal Cancer project she is leading. The objectives of this project are to determine if co-targeting HER3 and KRAS is efficacious in KRAS mutant colorectal cancer and delineate adaptive responses to treatment.
“Despite treatment advances targeting mutant KRAS, colorectal cancer in the metastatic setting is typically incurable,” she explained. “Molecular profiling of patients’ tumors is commonplace in the clinic, and more patients with KRAS-mutant and HER3-mutant cancers are being identified than ever before. However, there are currently no approved therapies for this CRC subtype. Thus, we aim to identify the most effective treatment options for this population.”
While expressing the significance this funding holds for the project, Dr. Garrett also shared how influential her Cancer Center membership has been for her work.
“The grant will be extremely instrumental to further our efforts to determine if co-targeting HER3 and KRAS is efficacious in KRAS-mutant colorectal cancer and delineate adaptive responses to treatment,” she said. “In addition to this funding, my Cancer Center membership has been crucial as I have previously received pilot funding to advance other projects and obtained extremely worthwhile collaborations through this membership.”
Hepatocellular carcinoma (HCC), or liver cancer, occurs when a tumor grows on the liver. HCC is responsible for over 12,000 deaths per year in the United States, making it one of the most serious cancers in adults as well as the predominant form of liver cancer. The etiology, or the causation, of HCC increasingly features non-viral factors. In patients with unresectable HCC, there is likewise a lack of reliable ways to guide and/or assess treatment response.
“We study alternatively spliced tissue factor (asTF), a secreted protein that triggers outside-in signaling via integrins,” said Dr. Bogdanov, an Associate Professor in the Hematology & Oncology Division of the University of Cincinnati’s College of Medicine. “We are the only laboratory in the world that studies asTF in gastrointestinal diseases.”
While their asTF-focused research has thus far focused on pancreatic ductal adenocarcinoma (PDAC), Dr. Bogdanov and his team recently discovered that asTF protein is elevated in the systemic circulation as well as liver tissue of pre-HCC (cirrhosis) and HCC patient populations. They also discovered that asTF activates pro-fibrogenic pathways and promotes leukocyte infiltration of the liver - the key processes that contribute to HCC progression.
“Our lab studies asTF as a biomarker and a therapeutic target in pancreatic cancer,” Dr. Bogdanov explained. “We recently developed a first-in-class biologic drug that targets asTF, and the drug already shows efficacy in preclinical models of pancreatic cancer. With the help of this funding, we will determine if asTF is also a key protein in the development and progression of liver cancer.”
Dr. Bogdanov will be using this award to support the Alternatively Spliced Tissue Factor as a Novel Biomarker and Therapeutic Target in Hepatocellular Carcinoma project he is leading. The focus of the project is to investigate the significance of a protein termed alternatively spliced tissue factor, or asTF, in the development of liver cancer. The new data this project will provide will hopefully assist in preparing a larger, competitive grant application.
“Key pilot data is required to take any new project to the next level, and this award will enable us to work on generating such data,” he said. “This pilot funding will allow us to carry out key studies that would otherwise be difficult to do. asTF acts via integrins in ways that, until recently, were very poorly understood. We hope that, in the longer term, our work will help patients suffering from cancer while, at the same time, improving our knowledge of how the interaction between integrins and the coagulation system drives cancer progression.”
While expressing his appreciation for this award, Dr. Bogdanov also took the time to note how his membership with the Cancer Center helped develop and advance the research he and his team are doing.
“Many, if not most, of my lab’s achievements while at the University of Cincinnati might not have been possible without the Cancer Center’s support,” he shared. “My Cancer Center membership helped me in a multitude of ways. Most significantly, it provided pilot funding, a rewarding intellectual environment, and the ability to establish and maintain terrific collaborations.”
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