Dr. Rehana Qureshi
University of Miami
“Estrone contribute to ER+breast cancer progression in obese postmenopausal female through immune evasion”

There is currently an obesity epidemic, with obesity in 40% of the USA female population. Obesity confers a 1.4 fold higher risk of developing postmenopausal ER+ breast cancer and a 2-3 fold higher risk of death [8]. These studies will test the effects of estrone and estradiol on breast cancer progression in the context of obesity. This grant’s focus on molecular events altered with changing estrogen type and levels in female physiology within the context of obesity and breast cancer progression is unique and might generate new strategies for prevention and therapy of ER+ breast cancer. A better understanding of the roles of estradiol and estrone in the context of obesity may lead to new strategies for breast cancer prevention and treatment and to changes in hormone replacement therapies. We will address how age, estrogens, exposure to immune challenge, and obesity may all play critical roles in shaping anticancer immunity. While current clinical trials have shown ER+ breast cancers are not very responsive to checkpoint inhibitor drugs, our preliminary data lead us to test if high estrone levels in postmenopausal obese women might present a novel rationale for effective use of these drugs. The proposed study has potential to reveal that estrone impairs anti-tumor immune responses through MDSC mobilization and other mediators to facilitate malignant progression. This study will provide mechanistic insight into how augmented estrone activity in the obese breast might contribute to tumor initiation and metastatic spread. It might also provide a novel rationale for testing the efficacy of combined therapy with antiestrogens and checkpoint inhibitors.

Dr. Inna Smalley
H. Lee Moffitt Cancer Center & Research Institute. Inc
“Defining and targeting the pro-tumorigenic metabolic microenvironment of leptomeningeal metastasis in
triple negative breast cancer” 

The goal of this work is to improve our understanding of the spread of triple negative breast cancer to the membranes covering the brain and the spinal cord, collectively known as the leptomeninges, and how tumor metabolism affects tumor survival and immune evasion in this unique environment. As we learn to better control the tumor at other sites of the body, this site of tumor spread is becoming more common. Unfortunately, we do not know much about the biology of the tumor at this site and the survival of patients with this disease is tragically short at 6-8 weeks. In order to adapt to the harsh environment of the leptomeninges, tumors that spread to this site typically undergo changes in metabolism, but it is currently unclear how these changes affect the infiltrating immune cells. We predict that tumor cells which spread to the leptomeninges also affect the metabolism of normal macrophages, a specialized type of immune cell that typically engages an immune response against the tumor. These changes lead to an alternative, pro-tumor function in the macrophages, supporting tumor growth and survival instead. In this project, we will determine if tumor metabolism specific to the leptomeninges affects the metabolism and function of macrophages and if we can target these metabolic changes with a drug to restore immune recognition of the tumor. These data will lay the groundwork for the development of therapies against triple negative breast cancer which has spread to the leptomeninges.

Dr. Smitha Pillai
H. Lee Moffitt Cancer Center & Research Institute. Inc
“Identifying metabolic vulnerabilities induced by acidosis in breast tumor microenvironment” 

It is well established that most solid tumors, including breast tumors, are acidic. Cancer cells must adapt to these acidic conditions in order to survive, thrive, and become invasive. We have shown that accumulation of lipid droplets (adiposomes) is a necessary adaptation for survival in acidic niches of tumors. Thus, measurement of these lipids in vivo can be a biomarker to identify tumors that are vulnerable to lipogenesis inhibition. We have observed that adiposomes accumulate under acidic conditions and inhibiting this is selectively toxic to acid- adapted cells. In this proposal, we will test the hypothesis that this phenotype is necessary for cell survival under acidic conditions in vitro and in vivo. In the first aim, we will determine whether the pharmacological inhibitors of lipid synthesis will inhibit acidosis induced adiposome accumulation and cell viability of in vitro grown cells and tumor growth and metastasis in orthotopic mouse models of breast cancer. Further, we will develop methods to quantitatively characterize the lipid biodistribution using non-invasive magnetic resonance spectroscopic imaging to identify image features associated with lipid rich and acidic regions and correlate with histological staining for tissue markers. Data from these methods will be combined to map and detect lipids from tissue sections. The proposed work will use established orthotopic breast cancer models (breast cancer cell lines such as MDA-MB-231 and metastatic derivative of MCF7 grown in mammary fat pads of mice) and buffer therapy (NaHCO3) to disrupt acidosis in the tumor microenvironment and the lipid phenotype. In addition, we will extend these studies to tumor tissues from patients available at Moffitt Cancer Center to determine the relationship between acidic and lipid rich areas in the tumor. The data generated from this study can be used to identify tumors with acid induced therapeutic vulnerabilities that will not be present in normal tissue.

Dr. Walter O’Dell and Dr. Karen Daily
University of Florida Board of Trustees
“Toward amelioration of cardiac mortality in breast cancer” 

Thanks to modern chemotherapy, HER2-targeted therapy and radiation therapy (RT), there are now over 3.5 million breast cancer survivors currently in the United States. However, each of these treatments contribute to increased risk for major cardiac events and early cardiac death. Early intervention with conventional heart failure therapies can improve survival in the majority of affected patients and if we determine that a patient is having severe heart toxicity early enough, their treatment can be altered to spare the heart further injury. Unfortunately, current clinical methods for measuring heart function with echocardiography cannot detect subtle, early changes in heart function. Fortunately, our team has recently shown that subtle changes during treatment can be confidently measured using 3D magnetic resonance imaging (MRI) and precise modeling of the heart. Using this approach, we compared changes in heart function between breast cancer patients who received standard RT versus those receiving proton therapy at the UF Proton Therapy Institute. From the first 9 patients we found that heart function consistently decreased as the radiation dose to the heart increased. When then looked at an additional patient who had a low starting value and had received a moderately high dose to the heart. Our  model predicted that this patients heart function would drop to a level that results in heart failure within 10 months of completing RT, and, unfortunately, she was in fact rushed to the emergency room for heart failure just 7 months after treatment. In that first study we only looked at the effects of radiation but our data indicated that many patients had decreased heart function before starting RT, likely due to the chemotherapy that they received before radiation. Under this FBCF award, we will acquire MRIs before and after chemotherapy, and 3-months after RT in 10 patients to learn more about early changes in heart function and how that leads to heart failure.

Dr. Kamran Ahmed
H. Lee Moffitt Cancer Center & Research Institute. Inc
“Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer”

The three most common cancers to develop brain metastases are melanoma, non-small cell lung cancer (NSCLC), and breast cancer. Compared with other sites of metastatic spread, the development of brain metastases portends a poorer prognosis. Screening brain  MRIs are currently recommended for non-metastatic patients with NSCLC and melanoma due to the prevalence of brain metastasis in these populations. However, brain MRIs are only recommended in metastatic or recurrent breast cancer patients when neurologic symptoms are present per National Comprehensive Cancer Network (NCCN) Guidelines. Patients with early screen- detected brain metastases are more likely to receive stereotactic radiosurgery which has better outcomes than whole brain radiation therapy. The objective of this grant will be to conduct a phase II study of screening brain MRIs in advanced, asymptomatic breast cancer patients separated by biologic subtype to determine the populations at highest risk for the development of brain metastases and potential brain MRI screening. Through early diagnosis, we will identify patients eligible for focused radiation treatment and regular brain imaging surveillance ultimately improving clinical outcomes in these advanced, metastatic patients.

Dr. Marilena Tauro
H. Lee Moffitt Cancer Center & Research Institute. Inc
“A dual epigenetic/autophagy inhibitor as a novel strategy to treat triple negative breast cancer” 

This proposal focuses on developing a novel molecule (SG3-014) that can simultaneously inhibit multiple targets that are important for cancer cell survival. In particular, we want to target triple negative breast cancer (TNBC) growth and metastasis. TNBC is a deadly subtype of breast cancer and often TNBC patient’s prognosis is grim. Furthermore, there are no targeted therapies available for the treatment of this disease and resistance to standard of care chemotherapy is common. From our preliminary data, we observed that SG3-014 is able to impair and significantly reduce TNBC growth by inhibiting MYC expression and blocking a survival program known as autophagy. Both MYC and autophagy are critical for TNBC cell survival. Our data show that SG3-014 is superior to another inhibitor of MYC (JQ1) and is extremely effective in killing TNBC cells. We believe theadditional effect of SG3-014 is via blocking the autophagy kinase ULK3. We herein propose to further test the  efficacy of SG3-014 in metastatic TNBC animal models and more fully investigate the role of ULK3 in regulating the autophagy program in TNBC. Short-term impact: We will define the efficacy of SG3-014 in TNBC pre clinical animal models. Studies focused on ULK3 will shed new light on a novel mechanism by which TNBC cells regulate autophagy and cell survival. Long-term impact: Autophagy is a self-regenerative process that breast cancer cells use to avoid death caused by chemotherapy and allows them to become resistant. Understanding the TNBC resistance mechanism and identifying a new target, ULK3, responsible for controlling the autophagy process will provide the rationale for the translation of SG3-014 into clinical trials. My multi-disciplinary team has extensive experience in translating drugs to the clinical setting. The proposed interactions with TNBC patients through Moffitt’s patient researcher forum will also ensure that the patient’s voice is heard when designing studies and discussing the results.

Dr. Perry Johnson
University of Florida Board of Trustees
“ Improving Breast Radiotherapy setup and delivery using mixed reality visualization” 

Safe and effective Breast Radiotherapy (RT) requires the reproduction of a specific patient posture and the precise alignment of the patent with an RT device. Any difference in these two aspects can lead to the underdosing the target or over dosing critical structures. Current methods to guide patent setup use either on board x-ray imaging or ceiling mounted cameras. The former increases patient dose and prolongs treatment time while the latter is limited by obstruction, poor ergonomics, and prohibitive cost. Thus, there remains a real opportunity to improve the se-tup process for breast RT that would benefit patients. To achieve this aim, we are developing a new concept for patient posture correction and alignment using mixed reality (MixR). MixR is the blending of physical and digital environments. It is best implemented using immersive technology like the Microsoft HoloLens that use a variety of sensors to map the surroundings, track objects, and render holograms at specific locations. Notably, these attributes are enabled while a user dynamically navigates a space, thereby affording natural viewing holograms.

In this work, we will use MixR to develop an accurate, efficient, cost effective and portable system for registering a patient with an RT device by using a hologram as an intermediary. The system will allow a user to view a patient and a reference hologram of their body surface both simultaneously and directly. The hologram will be registered with the RT device, thus, by matching a patient to their hologram, they are registered with the RT device. Such a system removes the need for expensive and restrictive external cameras and holds the promise to improve outcomes by increasing accuracy and safety while reducing set-up time and imaging dose. Our goal is to develop a fully featured MixR application for breast RT set-up while also providing tools, workflows, and preliminary data needed to establish viability and the framework for larger patient studies.

Dr. Deborah Altomare
University of Central Florida Research Foundation, Inc
“Importance of Fibroblast Growth Factor Receptor-4 (FGFR4) in Mediating Breast Cancer Metastasis”

Historically and up to present day, breast tumors are often characterized by histological features, including the presence/absence of estrogen receptor, progesterone receptor and clinically defined cutoffs for HER2 amplification. These features are important considerations for determining treatment strategies for patients with breast cancer. However, tumor heterogeneity and complexity is a major challenge for understanding underlying molecular alterations in breast tumors that can effect treatment response. With the advent of whole genome analysis, DNA- and RNA-based microarrays and RNA sequencing, researchers started more than a decade ago  to profile breast tumors for underlying molecular alterations to better differentiate and classifycancer subtypes by molecular signatures. One emerging tool for grouping molecular signatures, called PAM50, is increasing in use and is based on the expression of a panel of 50 key transcript (RNA) markers for determining tumor subtype. We are interested in understanding the correlation between a PAM50 grouping of upregulated genes in a HER2e (HER2-enriched) subtype that also exhibits upregulation of FGFR4 (fibroblast growth factor
receptor 4). Importantly  FGFR4 is one of the RNAs included in the PAM50 panel used to segregate breast cancer samples into subgroups. FGFR4 expression is low in normal breast tissue, but upregulated across different clinical groupings of breast cancer. In particular, there is a striking correlation with FGFR4 and the HER2e molecular subtype. We postulate that it is important to test convergence with HER2, since inhibitors for FGFR4 are in clinical development. The data from this study would provide justification for inhibitors of FGFR4 as a new therapeutic strategy for patients with recurrent metastatic breast cancer.

Dr. Ana Gomes
H. Lee Moffitt Cancer Center & Research Institute. Inc
“NADK as an essential metabolic adaptation of metastatic triple negative breast cancer” 

Breast cancer is the most common malignant disease that affects western women, and the most commonly diagnosed cancer in the State of Florida. While the primary tumors can often be cured by surgery and adjuvan therapy, metastases that arise from these primary tumors often can be undetected for long periods of time, are highly resistant to therapy and are the reason for more than 90% of breast cancer mortality. Thus, the ability to effectively treat breast cancer is largely dependent on the capacity to treat metastases. This is particularly important for triple negative breast cancers (TNBCs), which are a heterogenous group of breast tumors that are often associated with adverse pathological characteristics, poorer clinical outcomes and a lack of targeted therapeutic options. 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 adaptions are necessary to enable cancer cells to survive the arduous process that leads to metastases. We have identified the upregulated de novo NADP(H) synthesis as an essential metabolic adaption of metastatic TNBC’s. Here, we purpose on one hand to evaluate the potential of this pathway as a therapeutic target for metastatic TNBC’s. Together, this work has had the potential to unveil a new treatment option for metastatic TNBC’s and will lay the ground for the development of targeted therapies for late stage TNBC’s for which there is presently none.

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