University of Central Florida Research Foundation, Inc. - Dr. Otto Phanstiel
Immune adjuvant therapy for the treatment of triple negative breast cancer
While the localized survival rate is 91%, the average survival for patients with metastatic triple negative breast cancer (TNBC) is approximately 2 years. How these TNBC tumors create their specialized environment and keep immune cells at bay is the focus of this study. The idea is to hit the tumors where it hurts most…right in their metabolic addiction! To survive in vivo, the mutated tumor cells rely on specific signaling pathways and metabolic processes to fuel their uncontrolled growth and to establish immune privilege. This project will investigate the role of polyamine metabolism and transport in the development of TNBC. The team has developed novel immune cell boosters that empower the patient’s immune cells to clear their own tumor. These boosters work by suppressing polyamine metabolism and polyamine import in the tumor microenvironment. We have found a way to lower the polyamine shield these tumors use to keep anti-tumor immune cells away. Using polyamine blocking therapy and a PD1 inhibitor, the team has observed durable cures in their mouse models of TNBC. The goal here is to better understand how the immune cell landscape is altered and further optimize the therapy. A success here could lead to a transformative new immunotherapy as a first-line treatment to cure these hard-to-treat cancers and may have broad applications across numerous cancer types addicted to polyamine metabolites. Replacing the use of chemotherapy (toxic chemicals) with immunotherapy (self-healing) could also lead to fewer side effects and improve the quality of life of patients and their families.
University of Florida - Dr. Jianrong Lu
Design of immunogenic recombinant AAVs for breast cancer immunotherapy
Immunotherapy with immune checkpoint inhibitors has revolutionized cancer care in select cancer types. However, breast cancer generally does not respond well to such immune checkpoint blockade. A promising approach to enhance cancer immunotherapy efficacy is to induce immunogenic cell death (ICD) in cancer cells. Cancer cells dying of ICD robustly activate host antitumor immune responses, which attack remaining cancer cells and synergize with immune checkpoint blockade therapy. The goal of this proposal is to develop adeno-associated viruses (AAVs) that can induce ICD in breast cancer cells by intertumoral injection/infection. Such AAVs are promising valuable agents to enhance breast cancer immunotherapy.
H. Lee Moffitt Cancer Center & Research Institute, Inc - Dr. Nancy Gillis
Evidence-based monitoring of clonal hematopoiesis in treatment for breast cancer
Clonal hematopoiesis of indeterminate potential (CHIP) is defined by certain genetic mutations in the blood that can be acquired over time. This condition affects up to 45% of people with breast cancer, with the risk increasing as they age. CHIP has been found in breast tumor samples and is linked to poorer clinical outcomes. Additionally, chemotherapy and radiation used to treat breast cancer may accelerate the progression of CHIP. However, it is still unclear how often patients with CHIP should be monitored to detect signs of cancer progression or the development of new cancers, such as blood cancers. This study aims to develop mathematical models to help determine the best schedule for monitoring patients with breast cancer who have CHIP. By providing evidence-based recommendations, the goal of this work is to improve clinical outcomes while avoiding unnecessary, frequent testing for CHIP in these patients.
University of Florida - Dr. Brian Law
Isoform-Selective Disulfide Isomerase Inhibitors for Overcoming Drug Resistance
The proliferation and survival of normal cells is controlled by extracellular factors that act on cell surface receptors. Cancer cells pervert this system to grow under conditions that kill normal cells. How breast cancer cells re-wire their receptor systems is unclear, although receptors that drive cancer growth such as the receptor tyrosine kinases HER2, EGFR, and MET are often over-produced by breast cancers, as are the Wnt receptors LRP5 and LRP6. In contrast, Death Receptor 5 (DR5), which kills aberrant cells, is produced in normal cells but not in most breast cancer cells. We hypothesize that this “receptor triage” drives tumor growth, spread, and drug resistance, and is controlled at the level of protein folding of these receptors in the cellular endoplasmic reticulum (ER). These receptors contain numerous intramolecular bonds between Cysteine residues, termed disulfide bonds, that maintain receptor stability and shape. There are >20 enzymes (protein disulfide isomerases (PDIs)) that control disulfide bond formation. Our compounds termed Disulfide bond Disrupting Agents (DDAs) inhibit a small subset of the PDIs that are essential for cancer cell viability and play a key role in the aberrant receptor profile of breast cancers. Thus, DDAs downregulate receptor oncoproteins (HER2, EGFR, MET, LRP5 and LRP6), while simultaneously upregulating and activating DR5. This normalization of receptor expression results in death of breast cancer cells and kills human breast tumors growing in animal hosts. Conventional therapies act by altering the activity of individual receptors, but this frequently leads to drug resistance due to receptors that substitute for the inhibited ones. Since DDAs act broadly to normalize the expression of multiple receptors, DDAs may induce tumor regression and overcome drug resistance. The aims of this project are to determine the precise mechanisms of DDA action and establish their effectiveness and safety in animal models of breast cancer.
H. Lee Moffitt Cancer Center & Research Institute, Inc - Dr. David Morse
Tenascin-C targeted alpha-particle therapy for metastatic breast cancer
We will develop a peptide ligand that specifically adheres tightly to the extracellular matrix protein tenascin C (TNC). In future work, this ligand can be used to engineer a highly effective, systemically administered, a-particle emitting radiopharmaceutical targeted to metastatic breast cancer. Breast cancer is the most common cancer and second highest cause of cancer death in Florida women. Once breast cancer has spread beyond the primary tumor (metastasized) a high percentage becomes resistant to current therapies. Therefore, new- and effective-targeted therapies are greatly needed. TNC is present at high levels in breast cancer metastases but is not in most healthy tissues. A radiotherapy targeted to TNC will have high efficacy and low systemic toxicity. TNC has not been fully explored as a target against breast cancer metastasis. Although there are nanobodies that are selective for TNC, there are no peptide-ligands that are specific for TNC. Peptide-ligands are much smaller than nanobodies and have in vivo properties more like small molecules, such as rapid penetration into tumor tissue and faster clearance from the bloodstream, which is advantageous for radiotherapeutic drug development. Targeted a-particle therapy is an intensive research field with several ongoing clinical trials because of its great promise of successfully eradicating even sub-clinical metastatic disease. We have recently developed a melanocortin 1 receptor peptide ligand conjugated to an a-particle emitting radionuclide for melanoma targeted a-particle therapy and are testing this radiopharmaceutical in a phase 1 clinical trial at Moffitt Cancer Center. We will use the known antibody structures and current methods to develop a TNC targeting peptide ligand that is attached to a radiometal chelator and is ready for immediate development into an a-particle emitting radiopharmaceutical in future studies that will enable an application to the FDA for permission to conduct clinical trials.
University of Central Florida Research Foundation, Inc. - Dr. Needa Brown
Cold-to-Hot: Reprogramming breast tumor microenvironments
Breast cancer is the most commonly diagnosed cancer in women, with triple-negative breast cancer (TNBC) being one of the most aggressive and hardest to treat. Unlike other types of breast cancer, TNBC lacks targeted therapies, leaving patients with limited treatment options. A promising therapy called immune checkpoint inhibitors (ICIs) helps the body’s immune system fight cancer, but unfortunately, it does not work for all patients. One of the most overlooked factors in cancer treatment is age. Recent studies suggest that younger and older women may respond differently to breast cancer therapies due to differences in their immune systems and tumor biology. However, we still do not fully understand how age affects the immune response in TNBC. Our research aims to uncover how the immune environment of TNBC tumors changes with age and how this impacts treatment response. We will use advanced protein analysis to compare the immune profiles of breast cancer tumors in young and older mice. Additionally, we will explore whether activating a key immune pathway (STING) can enhance the effectiveness of ICIs, particularly in older patients. This research could lead to major improvements in breast cancer care. Identifying new biomarkers could allow doctors to predict which patients will respond best to immunotherapy. By understanding how the immune environment of TNBC changes with age, we can develop personalized treatments that work better for both younger and older patients. Additionally, our findings may lead to new combination therapies that improve the effectiveness of ICIs, particularly for older patients who currently have fewer treatment options. Because Florida has an aging population, these findings could have a significant impact on breast cancer patients in the state, as well as nationwide. By understanding how age influences TNBC and immune therapy response, our findings could lead to improved outcomes for thousands of patients both in Florida and beyond.
University of Florida - Dr. Ryan Kolb
Targeting ANGPTL4 in combination with immunotherapy in basal-like breast cancer
Basal-like breast cancer can be divided into subtypes, with basal-like breast cancer being the most aggressive with the worst prognosis. The most common therapies for basal-like breast cancer include surgery, radiation and chemotherapy. Targeted therapies are available for the small percentage of patients with a mutation in the BRCA1 gene. Immunotherapies have been recently approved but the response rate is limited. Therefore, it is important to develop new therapeutic approaches to improve patient outcomes. The goal of this proposal is to provide evidence for the potential efficacy of combining novel therapies targeting angiopoietin-like 4 (ANGPTL4) with immunotherapy to treat basal-like breast cancer. ANGPTL4 is a protein that promotes tumor blood vessel formation and is highly enriched in basal-like breast cancer. The combination of therapies that target tumor blood vessel formation with immunotherapy has been successful in other types of cancer. Here we will determine the role ANGPTL4 plays in basal-like breast cancer vasculature and test the efficacy of targeting ANGPTL4 in combination with immunotherapy in preclinical models of basal-like breast cancer. This research will provide a rationale for the further development of ANGPTL4 targeted therapies for basal-like breast cancer.
University of Miami - Miller School of Medicine - Dr. Mariana Cooke
The oncogenic DAG-PKC pathway as an actionable vulnerability in TNBC
Breast cancer is the most prevalent cancer among women in the U.S. and poses a significant health burden in Florida. Although overall mortality has declined due to improved early detection and treatment methods, it continues to rise in vulnerable populations, particularly among women of African descent. This reflects alarming racial health disparities within the Florida community that require urgent intervention through dedicated research strategies to promote health equity. Almost 15% of all breast cancers are classified as triple-negative breast cancer (TNBC), an aggressive subtype due to its high risk of spreading to other parts of the body (metastasis), making the disease incurable. Therefore, there is an urgent need to understand the molecular abnormalities associated with TNBC to identify effective biomarkers and novel therapies. This application stems from our novel findings that link TNBC development to the excessive production of a lipid called diacylglycerol (DAG). DAG enhances the activity of the oncogenic protein kinase C alpha (PKCa). Based on our preliminary data, TNBC cells display a hyperactive DAG/PKCa pathway. Indeed, abolishing the expression of PKCa reduces the ability of cancer cells to grow and spread, suggesting its crucial role in TNBC. We will inhibit DAG/PKCa signals either pharmacologically or genetically in TNBC experimental models to determine the effect on tumor growth and dissemination. Additionally, we will combine standard chemotherapy agents with a PKCa inhibitor to evaluate the effectiveness against debilitating tumor growth and metastatic spread. Overall, our studies will significantly enhance our understanding of the molecular basis of TNBC and contribute to developing innovative therapeutic strategies against this devastating disease. Ultimately, our primary goal is to fulfill the promise of health equity by addressing the racial and social inequalities that drive cancer-related disparities in the Florida community.
Nova Southeastern University - Dr. Jean Latimer
Ancestry-specific Changes to Breast Cells After Exposure to S. Florida Chemicals
There is an ongoing disparity in breast cancer (BC) outcomes for African Americans. In Broward County there are 7 zip codes that show higher frequencies of advanced stage BC (55%) than in the rest of the US (30%). There is a greater percentage of people of African ancestry (AA) or Hispanic Latino ancestry (HL) in these zip codes compared with other ancestries. North Miami Dade also shows elevated percentages of advanced BC and is highly representative of HL. Many explanations have been proposed to explain the higher disparity in AA populations for negative health outcomes in BC, but one that has not been well explored is the environment. We continue to be in an ideal position to study environmental impact that leads to transcriptome changes consistent with BC, because of our unique tissue engineering system for normal breast that establishes patient derived cultures (PDCs) with high success. These cultures develop into ductal structures resembling the breast plumbing system over weeks. We have established 49 PDCs (passages >13). These PDCs are derived from women of AA, non-Hispanic white (NHW) and HL ancestries. We hypothesize that these 3 groups will show differences in their response to arsenic or glyphosate. We show that there is a significant difference in arsenic sensitivity in AA vs. NHW breast PDCs in immune system and stem cell genes and major pathways of DNA repair. We will now expand our work to a subgroup of HL women in S. FL by exposing new cultures to these chemicals that are proven or highly probable carcinogens, and present in S. FL water (arsenic), agriculture or lawns (glyphosate). After exposure, RNA sequencing will be performed to look at gene expression changes that are consistent with early stages of malignancy, compared with untreated controls. This work will fill an unmet void involving the unique vulnerabilities of people of different ancestries to environmental chemicals and their subsequent risk for developing BC.