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University of Florida
Brian Law, PhD  
Name of Project: “Dual mechanisms of DDA antitumor activity: Induction of tumor cell apoptosis and vascular disruption”

Drug resistance and metastasis are major contributors to breast cancer mortality. This project investigates a promising new chemical class of anti-cancer drugs discovered by our research team. Novel treatment regimens will be tested in new breast cancer animal models that develops primary tumors and liver metastases. This will provide an assessment of the effectiveness of the treatments against both the primary tumor and liver metastases.  Proteins termed HER2 and EGFR are overproduced in a significant fraction of the most aggressive breast cancers. Rather than directly attacking the mature HER2 and EGFR proteins as existing approaches do, our drugs interfere with the production of these proteins and induce cell suicide selectively in cancer cells overproducing EGFR and HER2. Normal cells are unaffected by these drugs, by when engineered to over produce EGFR and HER2, cells become exquisitely sensitive, demonstrating the specificity of this strategy. Clinical HER2+ breast tumors exhibit a 40-100x increase in HER2 levels compared to normal tissues and are expected to be highly responsive to our regimen.

This is a fundamentally different therapeutic approach than current regimens using antibodies (e.g., Trastuzumab and Pertuzumab) and chemical inhibitors (e.g. Lapatinib) to neutralize the EGFR and HER2 proteins. Cancer cells gain resistance to these drugs through high expression of HER-family members EGFR/HER2/HER3 because these proteins have overlapping functions and if one member is inactivated, another can take over its function. In contrast, cancer cells with high levels of EGFR/HER2/HER3 are more rather than less sensitive to our treatment regimen. Our strategy inactivates the entire EGFR/HER2/HER3 cassette and blocks a key cancer cell survival pathway to selectively kill cancer cells. It is expected that because of the unique mechanisms of action of this therapy it will be more effective against cancer, overcome cancer resistance to therapy and be non-toxic.

 

University of Florida
Mansour Mohamadzadeh, PhD
Name of Project: “Novel Oral Targeted Breast Carcinoma Vaccine”

Breast cancer cells can be destroyed by the immune system by targeting and attacking foreign proteins. However, natural immunologic breast cancer rejection is rarely observed. Increasing tumor-specific immunity through a vaccine might be a useful anti-tumor strategy. Dendritic cells (DCs) activate anti-tumor-specific immunity. We propose to simplify breast cancer vaccinations by using probiotic bacteria that release DC-peptide fused to the breast cancer antigens. This targeted vaccine will be captured by mucosal DCs to protect against cancer. This vaccine will be orally administered and thus does not require a needle to be used in cancer patients. Therefore, we propose to take the DC targeting peptide we have already produced, link it to well-studied breast cancer antigens, called rat neu, legumain and β-catenin, and produce the breast cancer targeted vaccine by our novel probiotic bacteria. We will demonstrate the capacity of this probiotic vaccine strategy to elicit protective anti-tumor immunity in mice with experimental breast cancers. We have significant expertise in all aspects of such manipulations. These investigations may lead to the development of novel vaccines that not only prevent cancer, but also to treat it. This vaccine will likely be combined with currently available surgery, radiation and chemotherapy for maximal effect. As immune therapy has the ability to eradicate small numbers of cells, it has the potential to eliminate small pockets of metastatic tumor cells that are often responsible for relapses in patients initially thought to be disease free.

 

HLee Moffitt Cancer Center
David Morse, PhD
“Breast Tumor targeted fluorescence guidance for intraoperative margin assessment”

The goal of this research is to develop a fluorescent breast tumor targeted drug that can be imaged in real-time during breast conserving surgery (lumpectomy). Following administration of the drug to the patient, the fluorescence will “light-up” the tumor cells and guide the surgeon during tumor removal, ensuring that all tumor tissue is removed. The current standard of care involves a pathology exam of the removed tissue after the surgical procedure is completed to determine if the tumor was completely removed (complete resection), or if some tumor tissue was left in the patient (incomplete resection). Patients with incomplete resections will need to undergo a second surgical procedure (re-resection). Currently, surgeons are not always able to identify the extent of the disease leading to high re-resection rates where 20-50% of patients need to undergo a second surgery. The effect of this research will be to reduce the number of women that will need re-resection following the initial breast conserving surgery and potentially decrease the number of patients electing mastectomy due to concerns regarding reoperation. An estimated 35,000 reoperative procedures are performed each year after breast cancer lumpectomy due to undetectable breast cancer cells left at the time of surgery. Reoperation increases risk of complications, pain, cost, and delays other breast cancer therapy, but it is important in reducing the risk of recurrent cancer after treatment. We plan to improve breast cancer lumpectomy by adding a fluorescent tag to breast cancer cells. This will make residual cells visible under special fluorescent cameras and improve complete tumor removal at surgery. To accomplish this goal, we will make a fluorescently-tagged breast tumor specific drug and evaluate it using human breast cancer cell lines and mice bearing human tumor engraftments. We will study the tumor specificity, tissue distribution and survival surgery with and without fluorescence guidance.

 

University of Miami
Fangliang Zhang, PhD
Name of Project: “The role of Ate1-mediated Degradation of Cyclin D1 in Breast Cancer Progression” Amount Requested: $100,000

The progression of breast cancer (BC) is known to be promoted by the elevation of cyclin D1. While such an effect can be caused by dysregulations of the synthesis or degradation of cyclin D1, previous studies mostly focused on synthesis and much less on degradation. This gap of knowledge creates difficulty for our understanding of the causes of BC cancer progression. This is particularly an issue for estrogen receptor (ER)-negative cases, where the increase of cyclin D1 can be poorly explained by the known mechanisms. Our proposed study concerns an enzyme called arginyltransferase1 (Ate1). This enzyme performs a posttranslational modification called arginylation, which is the addition of an extra arginine to the N-terminus of a protein. Such modified proteins will quickly degrade according to a classic theory called the N-end rule. In our preliminary studies, we found that the protein level of cyclin D1 in BC cells is affected by Ate1, and that Ate1 is preferentially downregulated in high grade, ER-negative BC cells. Based on these data, we hypothesize that the degradation of cyclin D1 is controlled by Ate1-dependent arginylation, which affects the progression of BC particularly in ER-negative cases. Such a theory is totally new because it is a posttranslational modification that cannot be covered by previous studies based on DNA or RNA analysis. In our proposed study, we will use biochemical tests, cell-based models, and human patient samples to provide comprehensive evidence for this new theory. The results of our study will lead to a fundamental change in our understanding of the regulation of cyclin D1 protein, as well as how this process is hijacked in breast cancer cells. Our study will help to establish Ate1 as a novel diagnostic marker and will also aid in identifying novel therapeutic targets treatment of breast cancer.

 

University of Central Florida
Jihe Zhao, MD, PhD
“Eradicate Drug Resistant Breast Cancer using Novel Combination Therapeutic Strategy”

One of eight women will develop breast cancer that kills the most women cancer patients in Florida and across the US despite the advancement in anti-breast cancer therapies. One of the majorhurdles for the treatment failure is drug-resistant tumor relapse. One in five breast cancer tumors has too much of a bad protein named as HER2 present on the cell surface. Because of this, a HER2- destructive drug called Herceptin (a.k.a. trastuzumab) was developed and has been used clinically to treat HER2-positive breast cancer patients. However, even among early stage HER2-positive tumors more than one quarter of them develop resistance to the drug within as short as a year of the treatment resulting in tumor relapse. Even worse, up to three quarters of the late stage tumors resist Herceptin even if it is given in combination with chemotherapy. Such drug-resistance is a deepest concern given that Herceptin-based therapy remains the top choice for HER2-positive breast cancer patients. Therefore, there is an urgent need for finding a way to improve treatment against Herceptin-resistant breast cancer. Cerium oxide nanoparticles (CNPs), unlike most drug-delivering nanoparticles, possess their own anticancer activity without disturbing normal tissues. Our preliminary experiments using cell culture have shown that Herceptin, if used in combination with CNPs, can kill Herceptin-resistant breast cancer cells very effectively. This is very exciting because CNPs may be a great helper for Herceptin to eliminate Herceptin-resistant breast cancer tumors in vivo. This project aims to perform preclinical studies to validate in vivo efficacy of the Herceptin plus CNPs combination strategy. The tremendous potential of clinical application of such a strategy could revolutionize the management towards eradication of Herceptin-resistant breast cancer and save lives for the many patients.

 

University of Miami
Gaofeng Wang, PhD
Expanding the Therapeutic Window of BET Inhibitors by Vitamin C”

Developing new treatments and optimizing available cancer drugs could expand therapeutic options for breast cancer patients. BET inhibitors (BETi) are a group of promising cancer drugs that are currently under evaluation in clinical trials. However, severe dose-dependent toxicities also have been noted in phase-I clinical trials. If by any means breast cancer can be sensitized to BETi, lower doses could then conceivably be used in patient care. This research proposes to use vitamin C to sensitize breast cancer to BETi primarily based on the novel function of vitamin C in regulating DNA demethylation. Our preliminary data suggest that JQ1, an open source BETi, at a sub-therapeutic dose in combination with vitamin C successfully shrink the tumor and prevent metastasis in animal models. The toxicities of BETi could then be lessened by using lower doses of BETi in combination with vitamin C supplementation. Vitamin C is a safe and well-tolerated micronutrient that is suitable for oral delivery. Thus, it is not plagued by “off-target” effects that might impede clinical usage. Overall, this translational research could help accelerate the implementation of BETi therapy into the roster of future drugs that are useful in breast cancer treatment.

 

HLee Moffitt Cancer Center
Heiko Enderling, PhD
“Immunological consequence of single vs. fractionated ablative radiation in breast cancer”

Radiotherapy is part of the treatment plan for most breast cancer patients. Current radiation protocols are based on the maximally tolerable dose concept to eradicate as many cancer cells as possible. Increasing data suggest, however, that more radiation may not always be better, suggesting that radiation may stimulate additional biology that helps eradicate the tumor. It is increasingly appreciated that radiation can induce robust antitumor immune responses that contribute to better clinical outcomes. Pioneering experimental studies indicate that the strength of the induced immune response is dependent on the radiation protocol. This has initiated the quest for the optimal radiation dose and dose fractionation to maximize immune stimulation. To prospectively evaluate clinically every possible radiation dose and dose fractionation schema is clearly impossible. We here propose that we synergize our multidisciplinary expertise of radiation oncology, immunology, and mathematical oncology to learn from existing clinical data of patients treated with different radiation protocols, and use computer simulations to predict optimal treatment strategies. The major components of the proposed first-of-its-kind analysis are (1) to determine how the pre-treatment tumor-immune ecosystem in individual patients is altered during and after radiation; (2) to evaluate the dose dependency of RT-induced immunity in clinical samples; and (3) to predict the optimal RT schema for patients based on pre-treatment tumor-immune ecosystem composition. Moffitt’s single dose intraoperative radiotherapy for breast cancer and our highly innovative clinical study of stereotactic neoadjuvant radiation offer the unmatched opportunity to evaluate the immune infiltration into the tumor and in adjacent healthy tissue before and after radiation with different doses. Our multidisciplinary team can then develop a framework to prospectively predict the evolution of the tumor-immune ecosystem. These results will lay the foundation for the subsequent first clinical trial of immune-guided personalized RT.

 

HLee Moffitt Cancer Center
Haitao (Mark) Ji, PhD
Development of Cell Permeable Beta-Catenin/T Cell Factor Inhibitors for Treatment of Triple Negative Breast Cancer”

The residual triple-negative breast cancer (TNBC) cells after adjuvant therapy are heterogeneous and have a subpopulation of cancer stem cells that drive tumor growth, seed metastases, and induce cancer recurrence. To date, there is no effective targeted therapy for TNBCs. Compelling studies have indicated that hyperactivation of the β-catenin signaling pathway significantly contributes to TNBC cell migration, invasion, and metastasis. The β-catenin signaling pathway also maintains self-renewal of cancer stem cells, resulting in TNBC recurrence and drug resistance. The β-catenin/ T-cell factor (Tcf) protein-protein interaction (PPI) is a key downstream effector of the Wnt/ β-catenin signaling pathway. The aberrant formation of this PPI has been recognized as the major driving force for the hyperactivation of Wnt/ β-catenin signaling, and TNBC invasion and metastasis. In the preliminary study, we have designed and synthesized a series of peptide-based inhibitors that target the Tcf4 G ANDE binding site of β-catenin. These potent peptides can selectively disrupt the β-catenin/ Tcf interactions, while leaving other related protein-protein interactions that are important for the physiologic function of normal cells unaffected. However, the cell permeability of these peptide-based inhibitors is low. In this application, two specific studies are proposed to design and synthesize cell-permeable, potent, selective small-molecule inhibitors for the β-catenin/Tcf interaction and evaluate the potency and selectivity of new β-catenin/ Tcf inhibitors using highly relevant biochemical and cell-based assays. This application will address two overarching challenges of breast cancer research: (1) eliminate the mortality associated with metastatic breast cancer, and (2) determine why/how breast cancer cells lie dormant for years and then reemerge; determine how to prevent lethal recurrence.

 

University of Florida
Jianrong Lu, PhD
 “Exploring an EMT- Specific Vulnerability in Breast Cancer”

Tumor metastasis, relapse, and treatment resistance represent the main contributing factors to breast cancer mortality and constitute clinical challenges of paramount importance in breast cancer. Breast carcinoma cells can acquire increased invasiveness and survival advantages through a cellular process known as epithelial-mesenchymal transition (EMT). However, it is difficult to eradicate such highly malignant cells. Currently, there is no available therapeutic strategy to target EMT cancer cells. Through our molecular characterization of EMT, we found that cancer cells must downregulate the lysine acetyltransferase MOF in order to undergo EMT. But MOF plays a fundamental role in chromatin regulation and all cells require a critical threshold of MOF activity to survive/grow. Therefore, we propose that EMT cancer cells are hypersensitive to MOF inhibition. We will validate that pharmacologic inhibition of MOF can overcome tumor metastasis and drug resistance in mouse models of breast cancer. As new MOF inhibitors with increased selectivity and potency are under development, pharmacologic inhibition of MOF represents an innovative approach to target the specific vulnerability of EMT breast cancer cells. Such therapeutic strategy may have a revolutionary impact on reducing breast cancer progression, therapy resistance, and recurrence.

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