Nine UF Health Cancer Institute researchers have been awarded pilot funding for innovative cancer research projects that aim to advance our understanding of how cancer develops and resists treatment, as well develop novel strategies for preventing cancer and personalizing treatment.
Researchers will unravel cancer biology and disease mechanisms on the cellular and genetic levels, as well as explore novel strategies for drug delivery, cancer prevention and treatment. The projects address several types of prevalent and deadly cancers, including brain, colorectal, lung, pancreatic and pediatric cancers.
The pilot funding was awarded to researchers in all four of the Cancer Institute’s research programs. The new projects are designed to collect preliminary data required to test novel ideas with the goal of creating a foundation for larger studies.
“Pilot funding is one of the most important ways we move strong ideas into real-world impact,” said Dejana Braithwaite, Ph.D., associate director for population sciences at the UF Health Cancer Institute. “These awards give investigators the chance to generate early evidence, build meaningful collaborations and advance research across the cancer continuum in ways that can ultimately improve outcomes for patients, communities and health systems.”
The amount of newly presented data, concepts and creativity from UF Health Cancer Institute members is inspiring, said Rolf Renne, Ph.D., associate director for basic sciences.
“It is great to see so many new collaborations on innovative projects that will no doubt accelerate cancer research,” Renne said.
Learn more about the research projects below.
Cancer Control and Population Sciences
“The Future of Cancer Prevention: A Digital Twin Approach to Scaling Motivational Interviewing”
Stephanie Staras, Ph.D.
Professor, Department of Health Outcomes and Biomedical Informatics, UF College of Medicine
Nearly four in 10 cancers are preventable. Infections, including human papillomavirus (HPV), cause 10% of all cancers. A proven strategy, motivational interviewing, exists to help people adopt cancer prevention behaviors, such as smoking cessation, receiving vaccinations and decreasing alcohol use. Motivational interviewing is a patient-centered communication style that promotes behavior change with acceptance, empathy and empowerment. Yet, it is not widely available to patients in clinics due to the time-intensive training, challenge of unlearning strategies from medical trainings like no unsolicited advice giving, limited time during medical visits, and regular feedback needed for the clinician to continue using the method.
Advances in artificial intelligence provide an opportunity to create an autonomous system that could provide patients with motivational interviewing without burdening the health care system. We need to know, however, if these systems will be as effective as humans are in creating behavioral change.
To start this process, the research team aims to create a computerized, automated tool that helps parents consider the HPV vaccine for their children. The team chose to focus on the HPV vaccine because there is a safe vaccine available that prevents six types of cancer. Motivational interviewing can increase HPV vaccination rates, and the investigative team has expertise with HPV vaccination.
The researchers will create an AI digital twin designed to replicate the live interviewer experience in a web-based text format. AI technology can learn from conversations and be designed to understand and respond to language. The researchers will teach the AI technology how to respond to parents by providing it with training materials and written recordings of over 200 motivational interviewing calls by their human interviewers with parents. The AI technology will be called a digital twin once it behaves consistently with motivational interviewing principles using a gold-standard quality checking tool, provides accurate medical information and uses conversational patterns like human interviewers.
Next, the team will assess parents’ impressions of the digital twin to see whether it is a reasonable and trustworthy option to help parents make educated decisions about the HPV vaccine for their child. While the team is creating a digital twin for HPV vaccination, the platform and processes can easily be adapted to other cancer behaviors such as smoking cessation or alcohol use. The research team has multidisciplinary experts, including a parent of a child eligible for an HPV vaccine, to keep the focus on parents who will potentially benefit from creating the tool.
“Linking Quantitative Imaging, Molecular Profiles and Systemic Health to Improve Prognostic Stratification in Non-Small-Cell-Lung-Cancer”
Aline Fares, M.D.
Clinical Associate Professor, Division of Hematology and Oncology, UF College of Medicine
Lung cancer is the leading cause of cancer death in the United States and worldwide. Even when lung cancer is caught early and treated with surgery or radiation, up to 40% of patients have their cancer return. In patients with advanced disease, predicting who will respond to treatment remains a major challenge. Doctors use information about the tumor like its size, location and genetic mutations to estimate outcomes. However, this approach overlooks an important piece of the puzzle: the overall health of the patient’s body.
Years of smoking cause damage throughout the body beyond the lungs, weakening muscles, increasing fat around organs, hardening blood vessels and destroying lung tissue. These changes are visible on CT scans that patients already receive as part of their cancer care and may hold important clues about how well a patient will tolerate treatment and how their cancer will behave. At the same time, certain genetic changes in lung tumors, such as mutations in genes called STK11, KEAP1 and TP53, make cancers more aggressive and less responsive to immunotherapy treatments.
This project will use an artificial intelligence tool called OSCAR to automatically analyze CT scans from more than 2,000 lung cancer patients treated at the University of Florida. OSCAR measures muscle mass, body fat, blood vessel calcification and lung damage from routine scans without requiring additional tests, radiation or cost. The researchers will combine these body health measurements with each patient’s tumor genetics and outcomes.
The study aims to determine whether body health measurements from CT scans can predict which patients are at higher risk, beyond current staging systems. The team will also investigate whether patients with more smoking-related body damage are also more likely to have the aggressive genetic mutations that make lung cancer harder to treat. The study uses a large, varied patient population in Florida, a state with a significant smoking-related cancer burden. The findings could lead to better tools for personalizing treatment decisions and identifying patients who need closer monitoring, ultimately improving outcomes for people living with lung cancer.
Cancer Targeting and Therapeutics
“Chemically inducing synthetic lethality for glioblastoma therapy”
Zhonglin Liu, Ph.D.
Assistant Professor, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Glioblastoma is an aggressive brain cancer that grows fast and is hard to cure. Most patients live about a year after diagnosis even with today’s best care. A particularly severe form, called mesenchymal glioblastoma, is driven by a small set of master regulators that push cancer cells into a more invasive, treatment-resistant state. Many of these tumors have lost a natural brake called the KLHL9 protein that normally removes those cancer drivers.
To make the treatment, Liu’s team will first discover drug-like chemical handles that bind to KLHL9. They will then create a medicine and test how well it seeks out KLHL9-deficient glioblastoma cells while sparing normal tissue.
If successful, this work will deliver a new, more precise way to treat glioblastoma by exploiting a genetic change that many tumors already carry. Beyond glioblastoma, the same strategy could be adapted to other cancers, opening a path to smarter, safer medicines.
“Mechanisms causing post-translational modifications to cyclophlin D that drive mitochondrial permeability transition in cancer cachexia”
Russell Hepple, Ph.D.
Professor, Department of Physical Therapy, UF College of Public Health and Health Professions
Many cancer patients experience a complex metabolic syndrome known as cancer cachexia, characterized by involuntary loss of body mass that is not reversed with additional nutritional support. Cancer cachexia is particularly prevalent in patients with pancreatic cancer, with about 70% of patients developing it. A major component of cancer cachexia involves wasting of skeletal muscle, which in turn lowers patient quality of life (increases feelings of fatigue), reduces tolerance and efficacy of cancer treatments, and directly accounts for about 30% of all cancer-related deaths.
One of the hallmark features of skeletal muscle in cancer cachexia involves marked alterations in the function and reduced abundance of the cellular powerhouses known as mitochondria. Hepple’s lab is focused on a particular feature of altered mitochondrial function known as mitochondrial permeability transition, or mPT. A simple way of conceptualizing mPT is to think about it as mitochondria exploding. The resulting rupture of the outer mitochondrial membrane with this mitochondrial explosion releases a variety of molecules into the cell. This activates pathways that break down the proteins in the cell and promote inflammation.
Furthermore, mitochondria that have undergone mPT are targeted for degradation, meaning mPT leads to reductions in mitochondrial content within the cell. Notably, Hepple’s lab has shown that inducing mPT in skeletal muscle causes atrophy and that atrophy induced by exposing muscle cells to substances released from pancreatic tumor cells can be prevented by agents that reduce mPT. Furthermore, Ca2+ is the major trigger for mPT. Hepple’s team has shown that the amount of Ca2+ needed to trigger mPT in the skeletal muscle of mice carrying pancreatic cancer tumors and in patients with pancreatic cancer is reduced. That means it is easier for mPT to occur in skeletal muscle with cancer.
This project aims to discover mechanisms by which substances circulating in the blood with cancer (so-called circulating tumor-host factors) can increase the amount of mPT occurring in skeletal muscle. Hepple hypothesizes that several circulating factors known to cause muscle wasting in cancer cachexia make it easier for mPT to occur in skeletal muscle by reducing the amount of Ca2+ needed to induce mPT. Studies in other diseases, such as heart disease, where mPT is known to cause cellular damage have identified a protein called cyclophilin D responsible for determining the amount of Ca2+ needed to trigger mPT.
This project focuses on identifying alterations in cyclophilin D structure induced by circulating tumor-host factors in pancreatic cancer and identifying the signaling pathways that link circulating tumor-host factors to these structural changes in cyclophilin D.
The team will test whether these cyclophilin D structural alterations reduce the Ca2+ threshold for mPT in muscle cells. The team will identify alterations in cyclophilin D structure that occur in both a mouse model of pancreatic cancer and in pancreatic cancer patients. This will facilitate the successful application of the discoveries to develop treatments for muscle wasting in patients with cancer.
The long-term goal of the research is to help develop new treatments that can prevent muscle wasting with cancer. Ultimately, the team aims to improve outcomes of patients with cancer by increasing their tolerance to treatments and increasing the efficacy of cancer treatments, as well as reducing deaths that are directly due to muscle wasting in cancer.
“Unraveling the immunomodulatory effects of chemotherapy-induced senescence”
Mohammed Gbadamosi, Ph.D.
Assistant Professor, Department of Pharmacotherapy and Translational Research, UF College of Pharmacy
Ewing sarcoma is an aggressive childhood cancer. Chemotherapy fails in over 40% of patients, greatly increasing the risk of death. One reason for this failure is that some tumor cells enter a temporary dormant state in response to therapy. This dormant state is known as therapy-induced senescence. It protects the tumor from being killed by chemotherapy. One of the characteristics of these dormant cells is that they release signals that can either stimulate the immune system to attack the tumor or create an immune-suppressive environment that allows the tumor to survive in a temporal manner.
Despite its importance, the dynamics of therapy-induced senescence and its effects on immune responses remain largely unexplored in Ewing sarcoma. This project aims to define how short-term versus long-term therapy-induced senescence influences immune activity in Ewing sarcoma.
The researchers will examine gene expression changes, secreted signaling molecules and immune cell responses using molecular and cellular assays. By integrating these data, the team will generate the first mechanistic understanding of how senescent tumor cells modulate the immune environment in Ewing sarcoma.
These findings could provide mechanistic insight into how senescent tumor cells shape immune responses in Ewing sarcoma and potentially position therapy-induced senescence as an adaptive biomarker for predicting therapy response. Ultimately, the work could guide new strategies to reduce recurrence and improve survival for high-risk patients, including revealing optimal windows for intervention with new treatments targeting the therapy-induced senescence process. The resulting datasets will also enable future studies by Gbadamosi’s team and others aimed at translating these insights into novel therapies for this pediatric cancer.
Immuno-Oncology and Microbiome
“Regulation and impact of pks+ E. coli intra-host evolution in gut inflammation and colorectal cancer development”
Ye Yang, Ph.D.
Assistant Scientist, Department of Medicine, UF College of Medicine
Colorectal cancer is the third most common and deadly cancer type in the U.S. Importantly, the incidence and death rates of early-onset colorectal cancer, which is colorectal cancer diagnosed under the age of 50, are steadily increasing. A better understanding of the factors and mechanisms contributing to the development of colorectal cancer, including early-onset colorectal cancer, is critical for developing new preventive and therapeutic approaches.
Multiple factors affect colorectal cancer susceptibility, including genetics, diet, lifestyle, inflammation and microbiota. Gut inflammation, as experienced in patients with inflammatory bowel disease, increases the risk for developing colorectal cancer. pks+ E. coli, which carry clb genes responsible for the synthesis of the DNA-damaging toxin colibactin, are highly prevalent in patients with inflammatory bowel disease and colorectal cancer. DNA damage in gut epithelial cells can lead to the accumulation of genetic mutations and ultimately cancer. Unique colibactin-induced mutational changes are present in about 12% of colorectal cancer cases and enriched in early-onset colorectal cancer, suggesting that exposure to pks+ E. coli may contribute to colorectal cancer development and the rise of early-onset colorectal cancer.
Yang’s team has demonstrated that gut inflammation is essential for pks+ E. coli to drive colorectal cancer development in preclinical mouse models. However, it is unclear how the inflamed gut microenvironment modulates pks+ E. coli behavior to influence cancer development. Interestingly, Yang’s team discovered that along with the chronic inflammation and cancer development, pks+ E. coli evolved to become more motile and more potent at inducing DNA damage. Both activities are critical for bacteria to attack gut epithelial cells to drive colorectal cancer development. One such evolved E. coli isolate caused more colorectal cancer development than its ancestral strain in a mouse model.
Yang’s team hypothesizes that gut inflammation enhances pks+E. coli colorectal cancer-inducing activity by affecting bacterial evolution. In this project, the team will first use mouse models and perform genomic analyses to determine the impacts of healthy, inflamed and cancer gut microenvironments on pks+ E. coli evolution and identify E. coli genetic variants correlated with high cancer-inducing activities. The team will then colonize new mouse hosts with pks+ E. coli that have evolved within healthy, inflamed or colorectal cancer gut environments and evaluate the disease outcome.
The project will reveal pks+ E. coli genetic changes involved in the adaptation to the inflamed and cancer gut environment and the genetic variants associated with high cancer-inducing activities. By establishing the impact of pks+ E. coli intra-host evolution on colorectal cancer susceptibility, the team will identify novel targets for the prevention and treatment of pks+ E. coli-driven colorectal cancer and contribute to a new direction of research on the evolution of cancer-associated bacteria.
“Overcoming the Translational Challenge of Combination Immunotherapy using Multi-drug Nanotherapeutics”
Fan Zhang, Ph.D.
Assistant Professor, Department of Pharmaceutics, UF College of Pharmacy
Cancer treatments often fail because tumors use complex resistance mechanisms. Combining different immunotherapy drugs can help, but delivering multiple drugs together is challenging because they behave differently in the body and require complicated dosing schedules. Zhang’s solution is to create a single therapy that combines two powerful drugs using a tiny, engineered particle called a nanoconjugate.
This particle will carry both drugs in the right ratio to boost the immune system’s ability to fight cancer. STAT3 inhibitor is a drug that releases the brakes on the immune system from killing-tumor cells. STING activator is a drug that adds gas to the immune system to boost the killing of tumor cells. Zhang’s early studies show that pairing a STAT3 inhibitor with a STING agonist strongly stimulates immune cells. However, the best drug ratio for free drugs may not work the same way when packaged together, so the researchers will first find the optimal ratio for their nanoconjugate.
Next, the team will test how well this therapy works against tumors and whether it improves the effectiveness of existing treatments like immune checkpoint blockers. This research could lead to a new generation of combination therapies that are easier to deliver, more effective and help patients whose cancers resist current treatments.
Mechanisms of Oncogenesis
“Ancient survival programs in modern cancer: diapause mechanisms driving drug tolerance”
Rui Xiao, Ph.D.
Associate Professor, Department of Physiology and Aging, UF College of Medicine
One of the biggest challenges in treating cancer is that tumors often come back after therapy, even when the usual genetic causes of drug resistance are not found. Recently, scientists have discovered a special group of cancer cells, called drug-tolerant persister cells, that survive treatment by entering a temporary, sleep-like state. In this state, these cells grow slowly, lower their activity and become resistant to chemotherapy and stress, similar to how some animals pause their development during tough conditions.
To better understand how cancer cells enter and survive this dormant state, Xiao’s team studied a tiny worm called Caenorhabditis elegans, which naturally goes into a similar type of dormancy when it lacks food. This worm’s dormancy shares many features with the dormant cancer cells, including the ability to wake up and start growing again. Using this worm model, the team discovered a key gene called HLH-30 (similar to the human gene TFEB) that helps cells survive during dormancy.
Importantly, when the researchers reduced TFEB in human lung cancer cells that were drug-tolerant, these cells became much more sensitive to treatment and died more easily. This suggests that TFEB plays a crucial role in helping cancer cells survive in their dormant, drug-resistant state. The research highlights how studying simple animals like worms can reveal important clues about cancer cell survival.
Ultimately, this work may lead to new therapies that target dormant cancer cells and prevent cancer from coming back after treatment.
“Pancreatic cancer transformation potential of normal human pancreatic acinar cells following introduction of ‘Big 4′ mutations by gene editing”
Thomas Schmittgen, Ph.D.
Professor, Department of Pharmaceutics, UF College of Pharmacy
Pancreatic cancer is among the deadliest of all cancers. Once diagnosed, a patient’s life expectancy is typically measured in months. These dismal statistics reflect an inability to detect the cancer before it spreads, as well as ineffective therapies to treat the disease. The pancreas is composed mainly of acinar cells, which make enzymes to digest food. Acinar cells may change into another type of cell by a process known as acinar ductal metaplasia, which is one of the earliest steps in tumor development.
Using pancreas specimens obtained from organ donors who have died from natural causes, Schmittgen’s group has discovered that not all pancreases develop acinar ductal metaplasia to the same extent. Some develop it faster than others and their DNA instructs the cells to produce molecules like those seen in cancer. This project aims to develop a way to determine whether acinar cells from some individuals are more likely to turn into cancer than those from others.
Specifically, the team will study the epigenome, which acts like a set of chemical switches that turn genes on or off without changing the individual’s DNA. By sequencing DNA and RNA in normal cells and after these normal cells change to cancer, the researchers will be able to see what changes inside the cell as it turns into
cancer, helping them learn how to stop the process early.
The long-term goal of this work is to enhance our understanding of the early events in the development of pancreatic cancer and use this knowledge to develop tests to predict pancreatic cancer and develop new treatments.
Special thanks to our members who volunteer their time on this stringent review process and our research support staff for their hard work!
The UF Health Cancer Center’s pilot funding programs receive crucial support from the state of Florida through the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
