American Cancer Society Institutional Research Grant Awardees

2023 Awardees

 

Leonardo Ramos Ferreira, Ph.D.

Assistant Professor, Department of Microbiology and Immunology

Collaborators: Elizabeth Hill, Ph.D., Aguirre De Cubas, Ph.D.

Project: Repurposing regulatory T-cells to eradicate solid tumors using chimeric antigen receptors

Dr. Ferreira’s research focuses on converting one of cancer’s allies into one of its worst enemies. The immune system can be enhanced and engineered to treat cancer. Most cancer immunology research has focused on T-cells, adaptive immune cells that patrol our body and eliminate infected and cancerous cells. Chimeric antigen receptors (CARs) are designer molecules that redirect T-cells towards cancer cells to destroy them. CAR-T-cell therapy has been remarkably effective for blood cancers. Yet solid tumors, the deadliest type of cancer, remain refractory to CAR-T-cells. The hostile microenvironment of solid tumors is either impenetrable to CAR-T-cells or, if CAR-T-cells do enter, they become exhausted. However, there is a subset of immune cells that accumulate and thrive in solid tumors: regulatory T-cells (Tregs). Tregs suppress immune responses, helping solid tumors evade the immune system. Dr. Ferreira discovered that CAR Tregs engineered to recognize tumor cells kill them in the Petri dish. Can we turn Tregs against solid tumors? If we can repurpose Tregs into stealth bombers for solid tumors using CARs, they may become the first immune cell therapy to eradicate solid tumors.

 

 

Haluk Damgacioglu, Ph.D.

Assistant Professor, Department of Public Health Sciences

Collaborators: Ashish Deshmukh, Ph.D., Kalyani Sonawane, Ph.D., Evan Graboyes, M.D.

Project: Evaluation of multimorbidity, functional status, and financial toxicity among oropharyngeal cancer survivors

Oropharyngeal cancer (OPC) is one of a few cancers of which the incidence and mortality are increasing in the U.S. The more notable increases in OPC incidence were observed among older adults (~5%/year). Although OPC has excellent survival, OPC survivors have been experiencing late and long-term toxicity with subsequent functional impairment and a negative impact on quality of life after OPC treatment. In addition to treatment toxicity, OPC survivors suffer tremendous financial toxicity. Yet, to date, the functional status, associated multimorbidity, and financial toxicity among elderly OPC survivors have not been systematically characterized. This project will use data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to address these critical knowledge gaps. Our specific aims are: To evaluate the functional status and multimorbidity among older adults with OPC (Aim 1) and to estimate financial toxicity among older adults with OPC (Aim 2). Utilizing the validated algorithms, the project will capture the chronic medical conditions of OPC survivors, functional status, and OPC financial burden. The findings will help oncologists make informed treatment decisions considering the patient's overall health and well-being.

 

 

Amanda Palmer, Ph.D.

Instructor, Department of Public Health Sciences

Collaborator: Benjamin Toll, Ph.D.

Project: Comparing the effects of augmented doses of nicotine replacement therapy on quitting cigarettes and e-cigarettes

In the U.S., cigarette smoking is a leading cause of disease, such as cancer. Alternative tobacco products like electronic cigarettes (e-cigarettes; vaping) have grown popular. E-cigarettes may help some individuals quit smoking, whereas others may be unable to quit smoking and become “dual users” of both products. Because of the negative effects of smoking and vaping, many dual users want to quit all tobacco use. However, there are few scientifically supported treatments to help these individuals. The aim of Dr. Palmer’s project is to help dual users quit vaping and smoking using nicotine replacement therapy. Three doses of the medications (both patches and lozenges) will be tested to see which is most effective in helping dual users stop their tobacco use entirely. The results of this study will provide information for treatment providers and researchers about how to use nicotine replacement therapy for dual users of cigarettes and e-cigarettes. Improving tobacco cessation strategies for dual users will reduce the incidence of cancer in the future.

2022 Awardees

The goal of this project is to develop and launch a new training program for community health workers called KEEP IT (Keeping Each other Engaged Program via IT). KEEP IT is an innovative training for community health workers designed to build their competencies in using health IT tools to facilitate identification, screening, and access to genetic services among African American women who are at increased risk for hereditary breast and ovarian cancer.

Although recent studies have found higher prevalence of genetic mutations associated with hereditary breast and ovarian cancers among African American women, less than half of eligible African American women are assessed for genetic risk and only 28% engage in risk-reducing interventions. Community health workers are trusted members of communities with established relationships with individuals and families, so we hope that by empowering them with the right education, tools, and resources they can in-turn work with their clients to overcome common barriers. Our hope is that this training program helps move us closer to addressing cancer inequities and contributes toward growing efforts in reducing disparities in access to precision medicine.

 

Redirecting T-cells to directly recognize proteins on the surface of cancer cells using chimeric antigen receptors (CARs) has dramatically improved the remission rate of previously incurable cancers. A CAR is a man-made molecule that combines an antibody-derived fragment to recognize a desired cancer molecule and an array of T-cell signaling domains that instruct the CAR T-cell to kill cancer cells with the target molecule. The FDA has now approved five CAR T-cell therapies targeting CD19, a molecule expressed in B-cell-derived leukemia.

However, while success stories of CAR T-cell therapy curing liquid cancers abound, the same is not true of solid tumors. The solid tumor microenvironment has proven hard to penetrate to anticancer T-cells. And even to those T-cells that do manage to penetrate, the tumor microenvironment is inhospitable with its lack of oxygen and glucose, excess of lactic acid, and the presence of immune suppressive molecules and cells. One type of such immune suppressive cells are regulatory T-cells (Tregs). Tregs are a subset of T-cells dedicated to inhibiting immune responses, essential to preventing autoimmunity and tissue damage.

Yet, in the context of solid tumors, infiltrating Tregs signify a poor prognosis. What if we could repurpose these tumor Tregs and turn them against cancer cells? Tregs interact almost exclusively with professional antigen presenting cells, such as macrophages and dendritic cells, and have been reported to kill them in some instances as one of their many suppression mechanisms. I have redirected Tregs with an anti-CD19 CAR and found that they kill CD19-positive tumor cells in the Petri dish. This institutional American Cancer Society award will allow me to test whether CAR Tregs can successfully infiltrate and destroy solid tumors and dissect the mechanisms behind their killing activity, potentially leading to new strategies to eliminate solid tumors.

 

The development of prostate cancer heavily depends on the availability of circulating androgen. Androgen deprivation coupled with surgery is often an effective therapeutic method for prostate cancer patients. A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. Bone metastases develop in approximately 30% of patients with CRPC within two years of castrate resistance.

Mechanistic studies of CRPC bone metastases are key for facilitating the discovery of more effective treatments. PTEN deletions are found in 20-40% of localized prostate tumors and up to 60% of metastases. The purpose of my study is to elucidate the molecular mechanisms involved in CRPC bone metastases of PTEN null tumors. The long-term objective of my study is to understand the mechanisms that govern CRPC progression, and to devise new treatments for CRPC.

 

Fatty liver disease impacts a third of U.S. adults and can progress to liver cancer. This progression from healthy liver to fatty liver to cancer involves dramatic changes in the number of copies of the genome (DNA) per cell. The cues that guide increases and decreases in that DNA content (ploidy) are largely unknown.

In the first year of the award, our group successfully cultivated and characterized Caenorhabditis elegans (microscopic roundworms) with either two (normal, diploid) or four (tetraploid) genomes in every cell in their bodies. We found that the differences between these two states closely resembled what has been previously reported in the liver.

In this renewal application, we propose to follow up on this finding to use our worm model along with a three-dimensional liver cell culture model to better understand what is controlling the DNA content in healthy liver, diseased liver, and liver cancer. Altogether, our study will take advantage of the very powerful genetic model C. elegans to better understand the conserved biology of polyploidy and its role in cancer. 

 

Autoimmune diseases with persistent inflammation have been associated with increased cancer incidence. Systemic sclerosis is one such autoimmune disease with elevated risk for lung cancer. However, the process by which inflammation drives carcinogenesis is not known. Here, we aim to understand how persistent inflammation leads to DNA damage in pre-cancer cells and whether uncorrected DNA damage leads to mutations in cancer-driver genes.

Our work will provide a link between inflammation-induced genome changes and cancer in patients with systemic sclerosis. The proposal outcomes will fill a critical knowledge gap of a fundamental question in cancer biology by addressing the role of inflammation-driven genome-instability in driving carcinogenesis. Such information is important to develop earlier diagnostics and better therapeutic interventions for immune-mediated lung cancers.

 

The goal of the proposed study is to understand whether current smokers who have failed to quit smoking with traditional methods would benefit from trying to switch completely to a less harmful product, like e-cigarettes. Smokers who have previously failed to quit will be assigned to either 1) try to quit again with nicotine replacement therapy or 2) try to switch completely to an e-cigarette. Everyone will receive 5 weeks of medication or e-cigarettes, and everyone will choose a day to completely stop smoking within one week of receiving their medication or product.

During the study, we will collect information from the participants about their smoking and use of their assigned product, as well as a breath sample that measures whether the participants have recently smoked. The proposed trial will be one of the first trials in the United States to directly compare e-cigarettes for complete switching to FDA-approved pharmacotherapy for smoking cessation.

 

2021 Awardees

We aim to study the anti-cancer effect of low dose blood thinners after major gastrointestinal cancer surgery and disparities in the use of these blood thinners. Patients undergoing surgery for gastrointestinal cancers are at increased risk of blood clots (deep vein thrombosis and pulmonary emboli) which may cause serious health consequences. As a result, cancer organizations such as the National Comprehensive Cancer Network recommend consideration of preventative dose blood thinners for 30 days after major cancer surgery.

While these medications have been shown to decrease the occurrence of blood clots in clinical trials, basic laboratory research suggests that certain blood thinners such as enoxaparin may also have an anti-cancer effect with potential impact on cancer-related survival. However, our understanding of the association between enoxaparin use and cancer-related survival in humans is limited. Our team will use a national cancer registry to evaluate whether patients receiving enoxaparin have improved cancer-related survival. We will also evaluate the association of social determinants of health such as race and geography on the usage of enoxaparin. This study has the potential to improve the care of our cancer patients and mitigate disparities in the delivery of cancer care.

 

Monocytes are members of our inherited immune system and significant initiators of anti-tumor immune responses. As such, they are reported to support tumor growth by suppressing the adaptive immune system. When omitted, they are potent initiators of anti-tumor immunity. Thus studying the impact of monocytes on cancer immunity is of great value. We tracked individual immune cells during anti-tumor immunotherapy in patients. We observed that increased circulating monocytes correlate with response. A deeper investigation of monocytes in patients responding to therapy revealed an enhanced fat metabolism. The focus of this ACS-IRG pilot study is how altered fat metabolism in monocytes affects their function in inducing anti-tumor immunity.

 

Cancer treatments such as chemotherapy and radiation are effective for destroying most cells within a tumor, but in many cases, a small number of resistant cells remain. Those resistant cells have unique properties: they are initially non-dividing, stress-resistant, giant cells that have extra copies of their genomes (called polyploidy).

When they eventually do divide, the recurring cancer is often more aggressive than the initial tumor. To better understand how those stress-resistant cells work, we are using roundworms called Caenorhabditis elegans that, when stressed, form larger animals that are stress-resistant and also carry extra copies of their genomes. Using innovative tools available to study these worms, we hope to find new ways to identify and target resistant polyploid cancer cells and improve cancer treatments.

 

Pancreatic cancer will become the 2nd most deadly cancer in the U.S. by 2030. Pancreatic cancer is defined by the presence of a KRAS mutation, which is mutated in 95% of pancreatic cancer patients. Of these, nearly 20% have the KRAS^G12R mutation. KRAS^G12R uniquely fails to regulate several metabolic programs previously assigned to mutant KRAS function. I have shown that KRAS^G12R cannot activate PI3Kα. Further, I showed that multiple PI3K isoforms are overexpressed in pancreas cancer.

This proposal seeks to define the role of the many PI3K isoforms in the pancreas. In addition, I have observed that KRAS^G12R cell lines are sensitive to the loss of the RALA and RALB small GTPases. RAL GTPases have been understudied in pancreatic cancer. Therefore, RAL signaling, in the context of KRAS^G12R, will be determined. This proposal uses KRAS^G12R to define the role of KRAS in the promoting of pancreas cancer. My research has shown that all KRAS mutations are not created equal. This proposal seeks to expand on that observation by defining KRAS^G12R-specific signaling. Data from these studies will be used to develop new targeted therapies for pancreatic cancer. 

 

An enzyme known as phosphofructokinase, platelet (or PFKP), which plays an important role in breaking down glucose to create energy, is important in clinical cancer research because its cellular expression level is associated with decreased survival rates in cancer patients. Preliminary data and analyses from Dr. Wang’s lab suggest that PFKP moves into the nucleus, which is the part of a cancer cell that contains its genes and controls its growth and production, to regulate leukemia, allowing it to spread throughout multiple organs and preventing the body’s immune system from recognizing and killing the cancer cells.

In this study, Dr. Wang’s lab will test how preventing the movement of PFKP into the nucleus affects the treatment of leukemia outside of humans. The study will also look at whether PFKP that is found in the nucleus can help predict whether a patient may develop an aggressive form of T cell leukemia.

 

2020 Awardees

2019 Awardees