H. Lee Moffitt Cancer Center & Research Institute, Inc – Dr. Martina Molgora
Impact of Obesity on Macrophage-Targeting Strategies in Breast Cancer
Immune checkpoint therapy, which uses antibodies to “release the brakes” on the immune system, has dramatically improved outcomes for some cancer patients, sometimes even leading to long-term remission or cure. However, for breast cancer, these treatments don’t work for many patients. For patients with metastatic breast cancer or hormone receptor–positive breast cancer, which are the most common and deadliest forms, current therapies are still insufficient. This highlights the urgent need for new combination therapies that can increase the proportion of patients who respond to therapy. This research focuses on targeting macrophages, a type of immune cell found in breast tumors, as part of a combination therapy strategy. Although targeting macrophages alone has failed, modulating their activity can enhance the effectiveness of other therapies. Recent studies have highlighted a subset of macrophages that express a receptor called TREM2. Targeting TREM2-positive macrophages is a promising strategy to enhance immune therapies for breast cancer. Here, we propose to address the impact of obesity on TREM2-targeting strategies. Obesity is a major risk factor and comorbidity for various diseases, including breast cancer. In fact, obese breast cancer patients have a more aggressive phenotype and a worse outcome. A key feature of obesity-related inflammation is the presence of lipid-associated macrophages. These macrophages often display characteristics that can induce immune cells suppression, and support tumor growth. Our preliminary data show that TREM2-targeting strategies are effective in lean models but fail under obese conditions. We aim to understand the mechanisms underlying these observations and to explore their implications for therapy. This proposal will examine how stratifying patients by BMI could guide macrophage-focused treatments, opening new opportunities to identify drug targets that modulate macrophage metabolism as a potential immunotherapy.
H. Lee Moffitt Cancer Center & Research Institute, Inc – Dr. Thordur Oskarsson
Mapping tetraspanin webs that control chemoresistance in dormant breast cancer
Breast cancer is often treated successfully at the primary tumor site, yet many patients develop metastases years later. This delayed recurrence occurs because a small number of cancer cells, termed disseminated cancer cells (DCCs), spread early to secondary organs and remain dormant, evading chemotherapy. These cells can survive for years without symptoms, only to later reactivate and form life-threatening metastases. Current treatments mainly target actively dividing cells, leaving dormant DCCs largely unaffected. Understanding how these cells survive and resist therapy is critical to preventing metastatic relapse. Our research focuses on two proteins, TSPAN1 and TSPAN8, which are highly active in dormant DCCs. These proteins do not function like typical receptors or enzymes; instead, they act as scaffolds that organize networks of interacting proteins at the cell membrane. Our studies show that TSPAN1/8 support metabolic adaptation which helps dormant cells survive chemotherapy. When TSPAN1/8 are blocked, these cells become sensitized to treatment. We aim to map all proteins that interact with TSPAN1 and TSPAN8 in dormant DCCs using advanced proteomic techniques. We will then test which of these interactions are essential for survival and therapy resistance using both three dimensional cell cultures and mouse models. Finally, we will compare our findings to human breast cancer data to identify which pathways are most relevant for patients. By revealing the molecular networks that protect dormant cancer cells, this project could uncover new strategies to eliminate them before they cause metastases. Targeting these proteins and their partners offers a novel approach to prevent breast cancer recurrence and potentially improve long-term patient survival.
H. Lee Moffitt Cancer Center & Research Institute, Inc – Dr. Vural Tagal
Coordinated Therapeutic Strikes along the Ploidy Axis
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer that often affects younger women and women in underserved communities. TNBC makes up about 15% of all breast cancer cases and is often difficult to treat, with only around 15% of patients surviving five years if the cancer has spread. Our project focuses on a new approach to help patients in Florida – especially those in underserved and rural communities – by personalizing treatment for TNBC. In rural areas, many women may not get early cancer care, which increases their risk of dying from breast cancer. Our goal is to change that by developing smarter treatments with a first-of-its-kind Software as a Medical Device (SaMD) that reach everyone who needs them. A key idea in this project is ploidy, which in simple terms means the amount of DNA in a cell. A normal cell has a typical amount of DNA, but cancer cells often have extra copies or missing pieces of DNA. You can think of it like cancer cells carrying extra baggage that normal cells don’t. This extra DNA (abnormal ploidy) can make cancer cells tougher to kill with standard treatments. By studying the DNA content of TNBC tumors, our team identified 6 drugs that selectively kills cancer cells with varying levels of extra DNA. Secondly, we are also creating “ploidy-aware” computer models–these are like virtual simulations of a patient’s tumor that take into account whether cancer cells have normal or extra DNA. Using these models, we can predict how the cancer might react to these 6 different therapies. With this information, we are exploring an extinction therapy approach. Instead of giving one fixed treatment plan to everyone, extinction therapy is like fighting a forest fire. First, we shrink the tumor as much as possible. Then, before the cancer can reignite, we deliver a second treatment that targets the remaining cells from a different angle. The goal is not just to slow the cancer down, but to eliminate it completely.
Mayo Clinic Jacksonville – Dr. Saranya Chumsri
AI-Enabled Spatial Single-Cell Immune Mapping in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer. Although new immunotherapy treatments combined with chemotherapy have improved outcomes, many patients still do not respond, and their cancer often returns. Currently, doctors cannot reliably predict which patients will benefit from these treatments, leading some patients to receive therapy that causes side effects without improving their chances of cure. Our research focuses on understanding how the immune system interacts with breast cancer inside the tumor itself. Instead of studying cancer cells in bulk, we will use advanced imaging technology that allows us to see individual cells and how they are arranged in the tumor. Our preliminary work shows that certain immune cells—called plasmacytoid dendritic cells—create “immune-active neighborhoods” that help the body recognize and attack cancer. Tumors lacking these immune structures appear resistant to treatment. In this Florida-based multi-institutional study, we will analyze tumor samples from patients with early-stage TNBC treated with modern immunotherapy. First, we will map immune cells and cancer cells at single-cell resolution to identify patterns linked to treatment success or failure. Second, we will confirm whether the presence and location of these key immune cells can serve as a practical biomarker that doctors can test using routine pathology methods. The goal of this project is to develop a reliable test that predicts whether immunotherapy will work before treatment begins. This would allow physicians to personalize therapy—directing effective treatment to the right patients while sparing others unnecessary toxicity, and guide development of new treatments for resistant tumors. Ultimately, this work aims to improve cure rates and quality of life for patients with aggressive breast cancer.
University of Central Florida Board of Trustees – Dr. Wencai Zhang
Metabolic Targeting of SDH to Block Metastasis in Triple-Negative Breast Cancer
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that often spreads early and has few effective targeted treatments. Our project focuses on a mitochondrial enzyme called succinate dehydrogenase (SDH). SDH helps cancer cells make energy and also controls chemical signals that can help tumors invade nearby tissue and travel to distant organs. We believe that dialing down SDH, or the helper proteins that assemble it, can weaken the machinery cancer cells use to spread. We will test this idea in two ways. First, we will switch off SDH or its assembly factors in TNBC cells and measure changes in invasion while checking that basic cell survival is not the main driver of any effect. Second, we will use new small-molecule SDH inhibitors designed in our lab and evaluate them in advanced models that grow directly from patient tumors. Because chemotherapy remains important for many patients, we will also test how SDH targeting drugs work with epirubicin and identify dosing schedules that are most effective and safe. Throughout the study, we will track clear markers in tumors to confirm that treatments hit their intended target and to identify which patients are most likely to benefit. If successful, this work will deliver a first-in-class strategy that focuses on stopping cancer spread rather than only shrinking primary tumors. The results could lead to new treatment options for people with TNBC, extend the benefit of existing therapies, and provide doctors with practical tools to match the right patient to the right treatment. Our ultimate goal is fewer metastases, longer survival, and better quality of life for patients and their families.
University of Florida – Dr. Thomas Burris
The use of ERR agonists to prevent Doxorubicin-induced Heart Failure
Over the past 50 years, breast cancer survival in the US has improved dramatically from about 75% to around 91%, representing one of the greatest achievements in oncology. However, as more women survive breast cancer, heart disease has become a leading cause of death among survivors. Doxorubicin (DOX), a standard and highly effective chemotherapy drug widely used to treat breast cancer, can damage the heart and lead to heart failure. Currently, there are no therapies to prevent this, forcing many patients to either reduce their chemotherapy dose or stop treatment entirely, potentially compromising their overall treatment plan. DOX harms the heart primarily by disrupting how heart cells produce energy. Normally, the heart utilizes fat as primary fuel, but DOX shifts it to a less efficient system that relies on glucose. This metabolic change severely weakens the heart’s pumping ability and eventually leads to heart failure. We developed novel drugs called ERR agonists that can restore normal energy production in the heart. In preliminary studies of high blood pressure-induced heart failure, these drugs prevented the loss of heart function and normalized energy metabolism. In this study, we will test whether these drugs can protect the heart exposed to DOX. Using rat models, we will determine whether these drugs can both prevent heart damage when given alongside chemotherapy and repair damage that has already occurred. The potential impact is far-reaching: this research could allow Florida’s breast cancer patients to safely receive full-dose chemotherapy, expand treatment options for those with pre-existing heart problems, and reduce long-term heart disease and non-cancer mortality among survivors. By addressing a critical barrier in cancer care and targeting the root bioenergetic causes of chemotherapy-related heart damage, this study aims to improve chemotherapy tolerability, long-term cardiovascular health, and overall quality of life and survival of patients.
University of Florida – Dr. Rodrigo Cristofoletti
Smart Trop-2 CAR-T with Synthetic Circuits for TNBC Precision
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer. It is called “triple-negative” because the tumor lacks three common markers that many breast cancer drugs target, leaving patients with fewer effective treatment options. TNBC also occurs more often in Black/African American and Latina women, contributing to long-standing disparities in outcomes. Many TNBC tumors display a surface protein called Trop-2, making it an important treatment target. The leading Trop-2 drug (Trodelvy®) can improve survival for some patients with advanced disease, but it can also cause serious side effects, including dangerously low white blood cell counts and severe diarrhea. These side effects occur because Trop-2 is also present on some healthy tissues. A major challenge is therefore how to attack Trop-2–positive tumors while better protecting normal organs. This project will develop a new type of immune cell therapy using T cells (a kind of white blood cell) that are programmed with a built-in safety rule. These cells will fully activate only when they detect a TNBC-specific context signal—either ROR1 or B7-H3—and Trop-2. In simple terms: (ROR1 OR B7-H3) AND Trop-2. This design is intended to focus the strongest immune attack on tumor-like environments and reduce damage to healthy tissues that may show Trop-2 alone. We will test this strategy using patient-derived TNBC “mini-tumors” grown on microchips that mimic real tumor conditions, drawing from an existing biobank that includes tumors from Black/African American, Latina, and Caucasian donors. At the same time, we will evaluate safety using a human gut-on-a-chip model that can detect early signs of tissue injury. The goal is to generate safer, more precise immune therapies for TNBC and a practical testing framework to speed the development of treatments with fewer side effects.
University of Florida – Dr. Sulma Mohammed
Silent Highways: Targeting the Lymphatic Network to Halt Breast Cancer Metastasis
Breast cancer most often spreads through the lymphatic system, the body’s natural drainage network. This makes the lymphatic system the earliest and most important pathway for cancer spread. Doctors use the sentinel lymph node, the first lymph node cancer reaches, to guide treatment decisions, but little is known about what happens to cancer cells before they arrive there. Tumor cells must first travel through tiny lymphatic vessels, where they are exposed to a special environment that may help them survive, avoid the immune system, and become more aggressive. Because these cells are rarely collected from lymph, this early and critical stage of cancer spread remains poorly understood. Our research in animal shows that the lymphatic system is not just a passive pathway but an active place where cancer cells change and gain stronger abilities to spread. Cancer cells found in lymph are different from those found in blood. They often form clusters, show stem-like features, and are much better at forming new tumors. This suggests that cancer cells may become more dangerous while traveling through the lymphatic system. Whether this also happens in women with breast cancer is unknown. This is important for two common types of breast cancer: invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). Both spread through lymph, but ILC often shows more lymph node involvement, even though its true risk of spread is often underestimated. This suggests these cancers may behave differently inside the lymphatic system. The goal of this project is to study, for the first time in women, cancer cells traveling through the lymphatic system and the environment they travel in. We will compare cancer cells in lymph and blood and study immune cells and signals in lymph fluid that may help tumors survive and spread. This work will enable the identification of early interventions to prevent metastasis before it becomes life-threatening.
University of Florida – Dr. Weizhou Zhang
FOXA1 in lobular breast cancer - Biology and Therapeutic Target
Breast cancer is the most prevalent and the 2nd lethal cancer among women. In 2025, an estimated 316,950 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S., along with about 42,170 women in the U.S. expected to die in 2025 from breast cancer. The death rate is relatively steady since 2007 suggesting novel breast cancer therapeutics are urgently needed to for saving patient lives. Invasive ductal cancers (IDC) represent around 85% of total breast cancer cases with virtually all therapeutics designed to target IDCs. Invasive lobular breast cancers (ILCs) consist of 15% breast cancer cases and all therapeutics are borrowed from IDCs, but with worse long-term prognosis and higher rate of endocrine resistance relative to IDCs. Here we chose FOXA1 as a target for marker development for endocrine therapy resistance and for drug development that can purposely degrade FOXA1. We have justified several scientific rationales to choose FOXA1 as a biomarker and therapy, due to the potential high efficacy in therapy resistance cases as well as the potential low toxicity since FOXA1 is not an essential gene for most other cancer types or normal cells. Our proposed studies use a high throughput screening technology to achieve the first proof-of-concept evidence for targeting and degrading FOXA1 for potential therapeutic development. This one-year project is expected to have the following milestone: 1) to establish the connection between FOXA1 and therapy resistance in ILC; 2) to achieve lead compounds that can effectively degrade FOXA1; 3) to validate the efficacy of such compounds in killing ILC cells in vitro or in vivo tumor models. The current effort is purposely aimed for next level of grant applications for potential clinical translation of treating breast cancer patients, likely a better and safer option than current treatment regimens in late stage ILC cancer patients.
University of Miami – Dr. Xiaodong Cai
Accurate and cost-effective AI prognostic models for breast cancer
Cancer prognostic gene signatures use gene expression values to predict cancer recurrence risk. They are crucial for personalized treatment, reducing over-treatment and side effects while enhancing efficacy. Commonly used in breast cancer (BC) clinical practice, the Oncotype DX 21-gene and MammaPrint 70-gene signatures, developed two decades ago, offer limited predictive power. Recently, we published an artificial intelligence (AI) platform that predicts cancer outcomes from tumor gene expression values, significantly outperforming existing methods across several cancer types. Our BC AI model offers higher accuracy at a lower cost, about $400 for the required gene expression data versus roughly $4,000 for Oncotype DX. In this project, we will use our AI platform to train AI models for predicting the outcomes of different BC subtypes using both tumor gene expression values and immune profiles. Since BC subtypes exhibit different recurrence risks and tumor immune profiles are predictive of cancer outcomes, our new AI models are expected to provide better prediction accuracy than existing models. Moreover, in contrast to the existing methods that use limited labeled data to train AI models for predicting cancer outcomes, our training algorithm can exploit both labeled and unlabeled data, which can further improve the prediction accuracy of the trained AI models. In addition, we will use our AI models to identify genes that significantly influence cancer outcomes and use a mouse model to validate these genes which can potentially serve as intervention targets for cancer therapy. The AI platform developed in this project will offer valuable tools and resources to the BC research community. Our AI models will provide accurate prediction of BC outcomes, facilitating personalized treatment. They will deliver accurate, cost-effective, and accessible clinical services for a diverse range of BC patients in the long term.