1. H. Lee Moffitt Cancer Center & Research Institute, Inc
Phase II Study of Risk Adaptive Screening in High-Risk Breast Cancer Patients
Kamran Ahmed
Current NCCN guidelines for systemic screening of breast cancer patients are vague and do not differ for those patients considered to be at high risk for recurrence compared to low risk. Patients with node positive disease following receipt of neoadjuvant chemotherapy and surgical resection are at a high risk of locoregional recurrence as well as distant recurrence. However, incidence rates for metastatic progression are not well detailed to identify those patients at sufficiently high risk to warrant routine CT chest, abdomen, and pelvis screening. Patients with early screen-detected metastases are more likely to receive stereotactic body radiation therapy as well as more aggressive systemic treatments to limit metastatic progression. The objective of this grant will be to conduct a phase II study of risk adaptive screening CTs in patients with high-risk node positive disease post neoadjuvant chemotherapy and surgery. Through early diagnosis, we will identify patients eligible for definitive management of their metastatic disease and routine systemic surveillance screening to decrease the morbidity and mortality associated with metastatic breast cancer.
2. H. Lee Moffitt Cancer Center & Research Institute, Inc
Effects of anesthetic agents on immune function and breast cancer progression
Aaron Muncey
Surgery under anesthesia is critical for the treatment of most breast cancer patients. During surgery several important changes occur in the body: 1) tumor cells shed into the blood, 2) the body has a stress response to surgery affecting immune function, and 3) certain anesthetic agents and pain medications suppress immune function. This temporary suppression may prevent the immune system from killing circulating tumor cells, disseminated tumor cells or emerging micro-metastases that develop into metastases. Since metastatic disease causes 75% of breast cancer deaths, it is critical to understand how commonly used anesthetic agents and surgical stress may promote metastasis. Animal models are an excellent way to study the effects of anesthetic agents on breast cancer progression as studies can be rigorously controlled in a way that is difficult to attain with human surgical patients, who have different tumor sizes, stages of breast cancer, co-morbidities, and anesthetic and pain regimens. The uniformity of animal models reduces subject variability and allows us to focus on the effects of the anesthetic agents in question, while also studying the effects of the stress response to surgery. We discovered that mice who received tail vein injection of lung tumor cells (Lewis lung carcinoma) under 30 minutes of anesthesia with either ketamine or isoflurane had increased metastases 2 weeks later when compared with control mice with no anesthesia. We plan to test these two common anesthetic agents again in the 4T1 mouse breast cancer model, which consists of a primary tumor that metastasizes allowing us to account for surgery and primary tumor effects. Mathematical modeling and altered timing of the experiments will help us identify where in the metastatic cascade the anesthetics exert their effect. The goal of this work is to identify unwanted effects of anesthetic agents on breast cancer progression and develop mitigation or prevention strategies.
3. University of Central Florida Research Foundation, Inc.
Natural Killer cells as an immunotherapeutic treatment for breast cancer
Alicja Copik
Non-responsive breast cancers, such as Triple Negative Breast Cancer (TNBC), which lacks druggable targets, remain challenging to treat, with a pressing need for innovative approaches. While immunotherapies have had some success, particularly checkpoint blockade targeting the PD-(L)1 axis, and improved the survival of breast cancer patients, most patients still do not respond. Recently, lack of response to checkpoint blockade was also correlated to low levels of Natural Killer (NK) cells, suggesting their utility as an adoptive cell therapy to increase treatment success. Another novel and promising area in drug development for breast cancer is targeting long-non-coding RNA (lncRNA), particularly MALAT1. This lncRNA was found to be involved in tumor pathogenesis, however, it is also expressed in NK cells. Yet, there is scarce, if any, knowledge of the role of MALAT-1 in NK cell function and anti-tumor response. This project will study the role MALAT1 in regulating NK cell function to understand the potential effects of MALAT1 therapeutic targeting on NK cells and/or the development of enhanced NK cell adoptive therapies for treatment of non-responsive breast cancers, such as TNBC.
4. H. Lee Moffitt Cancer Center & Research Institute, Inc
CD320-mediated vitamin B12 uptake in triple negative breast cancer
Ana Patricia da Silva Gomes
Breast cancer is the most common malignant disease that affects Western women, and the most commonly diagnosed cancer in women in the State of Florida. Among the different types of breast cancer triple negative breast cancers (TNBCs) are of particular interest as these heterogenous group of tumors are often associated with adverse pathological characteristics, poorer clinical outcomes and to date their treatment still relies on chemotherapy and radiotherapy regiments. This is especially problematic for older women with TNBCs, who are still often making the difficult decision of withstanding the harsh side effects of chemotherapies and consequent reduction in quality of life, or not undergoing treatment and have their lifespans cut short. Even though metabolic reprogramming is at the intersection of signaling pathways and their ability to elicit cellular changes to promote increased cell survival, growth and proliferation, we do not have a good understanding of which metabolic adaptations enable TNBCs to thrive and whether these can be targeted for therapeutic benefit, especially in the context of older TNBC patients. We have identified vitamin B12 levels and its transport into TNBC cells as an essential metabolic adaptation of TNBCs. Here, we propose on one hand to characterize vitamin B12 uptake in TNBCs across the different stages of tumor progression, and on the other hand to evaluate the therapeutic potential of blocking vitamin B12 uptake by TNBC cells especially in the context of old age, where systemic vitamin B12 deficiency is predominant. Together, this work has the potential to unveil a new treatment option for TNBCs and will lay the ground for the development of targeted therapies for TNBCs for which there is presently none, a particularly important step towards impacting TNBCs prognosis as well as quality of life especially relevant for older TNBC patients.
5. University of Miami
Epigenetic optimization of SERD therapy for obese breast cancer patients
Gaofeng Wang
Each year, more than 15,000 women in the State of Florida and nearly 300,000 women in the US, are diagnosed with invasive breast cancer. About 70% of all breast cancer cases are of the HR+/HER2- subtype. Overweight and obese women have a much higher risk of breast cancer, especially of the HR+/HER2- subtype. Selective estrogen receptor degrader (SERD) therapy, as one type of endocrine therapy, is effective in treating HR+/HER2- breast cancer. However, obese breast cancer patients are less responsive to SERD therapy. In preliminary studies, we identified that vitamin C sensitizes breast cancer cells to the SERD drug fulvestrant. It is noteworthy that obese patients have a much higher prevalence of vitamin C deficiency. In turn, SERD therapy promotes weight gain which could further worsen vitamin C deficiency and the outcomes of SERD therapy in obese patients. This study aims to determine if vitamin C improves the therapeutic outcome of SERD therapy for obese patients with breast cancer. Vitamin C is safe, readily available and translational to patient care. If vitamin C can successfully improve the therapeutic outcomes of SERD therapy in preclinical models, including PDX models as proposed, this will support a similar therapeutic strategy of using vitamin C for patient care. By applying vitamin C to sensitize breast cancer, standard SERD therapy could then be readily used to achieve an increased therapeutic index in patients. Results of this research will contribute to future clinical trials of incorporating vitamin C into SERD therapy to treat obese patients with metastatic HR+/HER2- breast cancer.
6. University of Florida
Cardiovascular Adverse Events Related to Aromatase Inhibitors in Breast Cancer
Marwa Tantawy
This study delves into the heart-related issues linked to treating early-stage breast cancer (BC) with aromatase inhibitors (AIs). While AIs effectively combat hormone receptor-positive BC, their impact on heart health remains unclear, posing potential risks. Specific patient groups are experiencing higher rates of heart-related issues, prompting an exploration into the influence of genetic factors. The lack of this knowledge hinders personalized treatment, making it challenging to optimize outcomes and minimize adverse effects. The study aims to fill this research gap by 1) Exploring Incidence and Mortality: Investigating how often AI-related cardiovascular adverse events (AI-CVAE) occur and their impact on diverse racial and ethnic groups in Florida and the U.S. This involves using data from the OneFlorida+ Clinical Research Network (OneFlorida) and the All of Us Research Program (AoU). 2) Identifying Genetic Variants: Examining the genes of individuals from diverse backgrounds to pinpoint specific genetic factors contributing to AI-CVAE. This involves genome-wide association studies within the AoU. 3) Deciphering Pathway Mechanisms: Understanding the detailed mechanisms underlying AI-CVAE by using human-induced pluripotent stem cells (hiPSCs). These cells will be transformed into heart cells in the lab and treated with AIs to simulate real-life scenarios. Anticipated outcomes include insights into the occurrence and mortality implications of AI-CVAE across diverse BC populations by using real-world databases such as OneFlorida and AoU. Ultimately, these findings will advance our understanding and management of AI-CVAE complications in BC on a personalized level, improving long-term patient outcomes. A key conceptual innovation is the study's pioneering approach to establishing the incidence of these issues across diverse racial groups, uncovering genetic associations, contributing to finding novel biomarkers, and providing more tailored and effective care.
7. H. Lee Moffitt Cancer Center & Research Institute, Inc
Iron-induced metabolic liabilities of breast cancer dormancy
Didem Ilter
Breast cancer is the most common malignancy affecting women in the United States and in the state of Florida. Breast cancer mortality is mainly caused by metastases that arise from the primary tumors. The prospect of eradication of breast cancer is dependent on our ability to prevent or cure metastases, which are highly resistant to therapies. Disseminated breast cancer cells can stay in a non-proliferative dormant state in the body of a breast cancer patient even after the primary tumor is successfully treated; their reactivation leads to recurrent metastatic disease and presents a clinical challenge. These dormant cells need to metabolically adapt to be able to survive; however, these adaptations usually come at a cost for the cancer cells leading to metabolic vulnerabilities. We aim to discover liabilities of these dormant cancer cells to inform therapeutic strategies that can eradicate these cells and thereby cure breast cancer.
8. University of Central Florida Research Foundation, Inc.
Characterization of FGFR4 in breast cancer tumor microenvironment
Deborah Altomare
Breast tumor heterogeneity is a major challenge for understanding molecular alterations that can effect treatment. Our laboratory has been studying FGFR4 (fibroblast growth factor receptor 4) in breast cancer cells with a HER2e (HER2-enriched) molecular subtype. There is a lack of understanding of tumor heterogeneity within the HER2e subtype, which can include hormone receptor (HR)-negative or HR+ tumors with the capability to respond to HER2 targeted therapeutics. High FGFR4 protein activity could be a mechanism of therapeutic resistance, as our lab has shown for Lapatinib-resistant breast cancer cells. Moreover, studies in other tumor types suggest that FGFR4 RNA expression is a marker of immune cell response and/or that FGFR4 protein expression is associated with increased expression of PD-1 to suppress immune response against tumors. The study of these aspects requires a system to analyze interactions between tumor and immune cells. Even patient derived tumors engrafted into mice lack a functional immune system. In this exploratory study, we propose to use murine metastatic breast cancer cells that can be genetically manipulated for high and low FGFR4 expression and grown in a mouse with a functional immune system. Aim 1 will test if high FGFR4 expression contributes to increased metastasis of murine mammary tumor cells (e.g., increased tumor proliferation, rate and/or number of metastatic nodules). Aim 2 will test if FGFR4 expression is associated with an immunosuppressive microenvironment using human breast tumor tissue arrays and murine tumors from Aim 1. The overall objective is to determine the impact of FGFR4 on breast metastasis and whether there is an association between FGFR4 and tumor immunosuppression. This study will provide justification for future testing of FGFR4 inhibitors in combination with anti-PD1 or equivalent immune checkpoint inhibitors as a new therapeutic strategy for patients with relapsed, recurrent or metastatic breast cancer.