2018 Scientific Grant Awards
February 1, 2018 - January 31, 2019
Sanford Burnham Prebys Medical Discovery Institute
Dr. Mansanobu Komatsu
"Role of R-Ras in immunostimulatory tumor microenvironment"
Checkpoint immunotherapies have recently become an extremely promising strategy for cancer treatment because this type of cancer therapy have shown the complete cure of malignant cancers in some patients. An important advantage of immunotherapy is that it causes relatively few significant side effects compared with chemotherapy. However, only a fraction of breast cancer patients have responded to immunotherapies to date. The success of checkpoint immunotherapy depends on patient’s own immune cells, which fight against cancer cells and kill them. In particular, T cells are immune cells primarily responsible for anti-tumor immune activity and have a potential to eradicate breast cancer cells. However, cancer cells create a type of environment around themselves that inhibits the T cells from penetrating into the tumor interior. If we can remodel the tumor environment in such a way that T cells can penetrate into thetumor, immunotherapies could work for most, if not all, patients. High endothelial venues (HEVs) are a type of blood vessels specialized for recruiting T cells to the site of chronic inflammation. HEVs are also known to form in some cancer patients’tumors and serve as a gateway for T cells to enter the tumors and destroy the cancer cells. Indeed, significant clinical evidence indicates that the formation of HEVs is associated with favorable prognosis. However, little is known about the mechanism of how HEVs forms in tumors and how this formation can be therapeutically induced. The proposed study is aimed to determine the molecular mechanism of HEV formation and explore a potential strategy to improve checkpoint immunotherapy by enhancing HEV formation and T cell recruitment to malignant breast tumors.
H. Lee Moffitt Cancer Center & Research Institute, Inc.
Dr. Eric Lau
"The regulation of EGFR and MET signaling by fucosylation in triple negative and luminal breast cancers"
Survival rates for advanced breast cancer (BCa) patients are a clinical problem, as is the development of resistance to therapies. Thus, it is essential to improve our understanding of molecular mechanisms underlying BCa biology.
Receptor tyrosine kinases (RTK’s) on the cell surface communicate with proteins (including other RTKs) to mediate cellular responses (e.g. movement, proliferation, etc.) to environmental changes. Aberrant RTK communication drives BCa progression and drug resistance. Despite efforts to therapeutically target RTK’s clinical efficacy is limited by our knowledge of how RTK’s communicate.
Cell surface receptors, including RTKs, can be modified and regulated by the sugar fucose via a process called fucosylation. The roles of fucosylation in cancer are unclear. We previously discovered that fucosylation is reduced in human melanomas. Increasing fucosylation by dietary fucose supplementation blocks tumor growth and metastasis, demonstrating that manipulating fucosylation is a feasible anti-cancer approach. In contrast to melanoma, we recently found that fucosylation is increased in BCa and correlates with survival of triple-negative (TN) or luminal BCa patients. Importantly, fucosylation appears to affect the communication of 2 RTKs, epidermal growth factor receptor (EGFR) and tyrosine protein kinase Met (MET), both of which mediate cancer growth and drug resistance. Modulating fucosylation appears to affect cell growth and enhances the BCa cell-killing by drugs that target these RTKs. Here we will test our hypothesis that fucosylation regulates EGFR and MET to drive TN and Luminal BCa growth and drug resistance. This is a unique opportunity to bridge the sugar and cancer biology fields, which is expected to result in i) novel insights into BCa biology and therapeutic responsiveness, ii)rationale for fucosylation based anti-cancer approaches , and iii) improved patient characterization/patient selection criteria for targeted therapies based on tumor/EGFR/MET fucosylation.
H. Lee Moffitt Cancer Center & Research Institute, Inc.
Dr. Brian Ruffell
"Targeting of the immune checkpoint molecule TIM-3 in Breast Cancer"
Effectively harnessing the power of the immune system is one of the most promising advances in cancer therapy. Immunotherapy takes advantage of the tumor killing capacity of cytotoxic T cells, and ability that is normally limited within the tumor via multiple suppressive pathways. Supporting the activity of these cytotoxic T cells can provide long term survival advantages, but despite recent successes, only a proportion of patients respond to immunotherapy , and efficacious treatment has so far been limited to select tumor types. The identification of additional therapeutic targets is urgently needed to address these issues and increase upon the number of patients who will benefit from this relatively safe and effective treatment approach. In preliminary studies, we screened for potential targets that may be attractive targets for immunotherapy, and identified the surface protein TIM-3. We have found that blocking TIM-3 indirectly enhances the activity of cytotoxic T cells within tumors, resulting in increased chemotherapeutic efficacy in murine models of luminal B and triple negative breast cancer. Here we propose to evaluate if TIM-3 blockade can improve response to radiotherapy or other immune stimulatory agents. We will also optimize the dosing regimen for TIM-3 blocking antibodies with chemotherapy and the efficacious combinations that we identify. The results of our proposed work have a high potential to impact if TIM-3 blocking antibodies, now entering phase I studies, will be utilized clinically in breast cancer.
H. Lee Moffitt Cancer Center & Research Institute, Inc.
Dr. Lixin Wan
"Energy Restriction -mediated PRC2 Inhibition to Guide Breast Cancer Therapy"
Breast cancer is one of the most deadly forms of cancer among women. To date, surgery followed by radio- and/or chemo-therapy is still widely used for the treatment of breast cancer, especially triple-negative breast cancers. The toxicity profiles of chemo- and targeted therapies have long been a major concern in designing therapeutic strategy for aggressive triple-negative breast cancer patients. Hence, a less toxic sensitizer will be of great value for treating breast cancer patients, and for improving quality of life. Multiple lines of clinical evidence indicate an anti-cancer effect of the anti-diabetic agent, metformin, on breast cancer patients, likely through the alteration of cellular energy status which activates the 5'-AMP-activated protein kinase (AMPK). Our preliminary studies revealed that AMPK activation in breast and ovarian cancer cells suppresses the oncogenic function of EZH2 via the direct phosphorylation on EZH2. EZH2 has been well characterized in promoting tumor cell proliferation and metastasis, EZH2 mutations or amplifications have been found in a broad spectrum of human cancers including breast cancer. Our findings hence suggest that activating AMPK by energy restriction agents could be utilized to harness EZH2 oncogenic functions in tumor cells. In support of this notion, we found a positive correlation between AMPK activity and EZH2 phosphorylation, and further revealed that higher EZH2 phosphorylation correlates with better survival in breast cancer patients. In the present proposal, we aim to identify the molecular mechanisms by which AMPK suppresses EZH2, and to investigate physiological role of the AMPKEZH2 axis in cells and in mouse. Furthermore, we will assess an anti-breast cancer therapeutic strategy by using metformin to sensitize breast cancer cells to chemo- or targeted therapeutic agents, which will provide rationale for using energy restriction agents to improve the efficiency of currently available therapies in EZH2 amplified or hyperactive breast cancer patients.
University of Florida
Dr. Yong Huang
"Printing of Three Dimensional Vascularized Breast Tumoroids for Drug Screening"
Cancer, including breast cancer, is still a major cause of death globally. Unfortunately, development of anticancer drugs is a demanding process in terms of cost and time, and approximately only one in ten drugs entering clinical trials finally becomes available to the public. The ability to predict the efficacy and toxicity of anticancer drugs earlier will save a significant amount of resources. The commonly used two-dimensional culture method of preparing cancer cells for drug discovery has proven to induce altered gene and protein expressions in cells. While animal models have also been used intensively, the use of animal models for drug testing has caused inaccuracy and high costs to predict human responses, safety, and efficacy. Herein we propose a novel hybrid printing-and-self-assembly approach integrating both complex three-dimensional biofabrication as well as cell sourcing towards the freeform fabrication of vascularized breast tumoroids. Such tumoroids can be utilized to investigate poorly understood cell-drug interactions that can contribute to much-needed drug discovery applications in breast cancer treatment. We envision that a patient specific breast tumor model can be explored as a much-needed reliable and cost-efficient in vitro platform to facilitate drug metabolism studies, preclinical drug screening, and other fundamental research. This transformational development would markedly reduce the high cost of drug development, now a major economical roadblock to sustained progress in healthcare, including breast cancer treatment.
University of Florida
Dr. Brian Law
"Synthetic Lethal strategy for Killing EGFR+/HER2+ cancers"
Drug resistance and metastasis are major contributors to breast cancer mortality. This project will test a novel combination therapy consisting of two drugs that synergize to kill breast cancer cells. The regimen will be tested in a new breast cancer model that develops breast tumors and liver metastases. This will provide an assessment of the effectiveness of the treatment against both the primary tumor and the 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 will interfere with the production of these proteins and induce cell suicide selectively in cancer cells overproducing EGFR or HER2. Normal cells are unaffected by this drug combination, but when engineered to overproduce EGFR or 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 functions. 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
Dr. Daiqing Liao
"Novel isoform selective HDAC inhibitor for enhancing cancer immunotherapy against breast cancer"
Breast cancer is diagnosed in over 1 million women worldwide (about 15,000 in Florida) each year. Although more and more patients with breast cancer have survived of the disease, over 450,000 patients (3,000 in Florida) die of this disease annually. About one third of invasive breast cancers progress to recurrent or metastatic disease, and 90% of breast cancer deaths are due to metastatic cancer in vital distant organs such as brain, liver and lungs. There are several major breast cancer subtypes: estrogen receptor-o positive (ER+), HER2-enriched and triple-negative (TNBC). All subtypes can progress to metastases. Although successful treatments have been developed, metastatic disease is currently incurable. The short median survival of 3 years for patients with metastatic breast cancer has not significantly changed in over 20 years. Therefore, more effective treatments are urgently needed to combat metastatic breast cancer. Cancer immunotherapy has revolutionized cancer patient care with unprecedented improvements in survival for a wide range of cancer types. Importantly, cancer immunotherapy is generally well tolerated and is not associated with cumulative toxicity of conventional cytotoxic chemotherapies. Certain adverse effects of cancer immunotherapy such as autoimmune responses can be managed in the clinic. However, most breast cancers generally do not respond to current cancer immunotherapy, although a small subset of patients, most notably certain patients with TNBC, derive clinical benefit from immunotherapy. Therefore, new drugs that can promote clinical response of breast cancers to immunotherapy may allow most breast cancer patients to reap clinical benefit from cancer immunotherapy. Our goal in this application is to assess the efficacy of SR-4370, a novel highly selective HDAC inhibitor, in combination with current cancer immunotherapy for treating TNBC that may not otherwise benefit from immunotherapy. Therefore, SR-4370 can be a potential drug that broadens breast cancer patient population that will benefit from cancer immunotherapy.
University of Miami
Dr. Judith Hurley
"Use of Virtual Reality to decrease chemotherapy associated anxiety, symptom distress, nausea, vomiting and fatigue"
When treating breast cancer, combination chemotherapy continues to be the current standard of care. The most common side effects of chemotherapy include nausea, vomiting, anorexia, fatigue and anxiety. Given the importance of chemotherapy in the treatment of cancer, the ability to reduce side effects and improve patient comfort during chemotherapy poses a significant advantage in promoting adherence and reducing treatment associated stressors. Up to 30% of patients experience anticipatory nausea and vomiting, which is generally not well managed with anti-emetic therapy. Patients who experience anxiety during initial chemotherapy treatment have been found to be more likely to experience anticipatory nausea. Therefore if interventions are introduced to reduce anxiety during chemotherapy, it may be possible to reduce the frequency and intensity of anticipatory nausea.
Non-Pharmacologic interventions provide alternative options to treat the side effects of chemotherapy. Virtual Reality (VR) is one such intervention that has gained public interest as an adjunct to medical treatment during chemotherapy over the past few years with several studies demonstrating that the use of VR during chemotherapy treatment decreases anxiety, distress, and fatigue in patients immediately after receiving chemotherapy.
Few studies evaluated the psycho-biological impact of VR on patients receiving chemotherapy therefore evidence of its benefits remains scarce. Based on this unmet need to determine conclusively whether intervention with VR is a valid complimentary non-pharmaceutical option for side effects management in chemotherapy patients, we will be conducting a study that measures physiological variables in response to VR therapy in association with chemotherapy. The study will look into whether the use of VR during chemotherapy treatment sessions decreases chemotherapy associated anxiety, symptom distress, nausea, vomiting and fatigue.
University of Miami
Dr. Tan Ince
"Multi-Hormone Treatment of Breast Cancer"
This application is responsive to 2017 FBCF Priority Area of “Understanding the links between environmental factors and breast cancer in Florida”. Our application is based on exciting new discoveries we made indicating that combining drugs that target receptors for estrogen (ER), androgen (AR) and Vitamin-D (VDR) can be a potent novel strategy to target breast cancer. While these receptors have been studied individually before, they have not been studied together in breast cancer. Combination therapy is essential to address resistance to standard treatments [1, 2]. However, since many drug targets are expressed in other tissues and normal cells[1, 2], it makes drug development difficult. Our approach is significant because the combined expression of ER, AR and VDR is rare in the body with breast epithelium one of the few tissues in which they are co-expressed [3-7]. Consequently, combined targeting HR provides a highly specific approach to inhibit breast CSCs. Importantly, our work can explain how environmental and life-style factors including stress, diet, exercise and hormones might influence BrCa. These effects cannot be explained from a genetic perspective because hormones do not cause DNA mutations. However, hormones do change how DNA is packaged, which determines which genes are “turned on” or “turned off.” The DNA, molecule so must be folded thousands of times to fit into the cell. This DNA folding process is partly accomplished by histone deacetylases (HDACs). We discovered that ER, AR and VDR work with DNA packaging proteins (HDACs), which can explain environmental influences on breast cancer that cannot be explained by DNA mutations alone. Importantly, we published that patients with BrCa that express all three HR (ER/AR/VDR) are seven-fold more likely to survive compared to BrCa that expressed none of these HR. This makes combined examination of ER/AR/VDR the most powerful predictor of outcome in BrCa .
University of Miami
Dr. Natalia Rodriguez
"Engaging and Education Community Health Workers to Promote Breast Health and Early Detection of Cancer among disadvantaged Spanish speaking female migrant workers in South Florida"
Breast cancer is the leading cause of death and disability in women un the United States and throughout the world. Evidence indicates that poor women, most of whom lack access to information on breast health and to treatment for catastrophic illnesses such as cancer, also suffer and battle barriers to access associated with migratory status, lack of education or steady income, and gender discrimination. These are the women who are most at risk of late detection and premature death, leaving entire families and young children with out a caregiver and at risk of spiraling into poverty traps.
Spanish speaking female migrant farm workers in South Florida suffer from lack of access to healthcare overall, as well as low breast cancer screening rates, very limited medical knowledge, and greater exposure to risk factors for breast cancer. Migrant and poor women also face significant cultural barriers that prevent them from seeking medical services for early detection of cancer, leading to late stage diagnosis and higher death rates.
Community health workers and community leaders have the ability to break down cultural access barriers by reaching out to communities in ways that other healthcare personnel cannot achieve. This proposal aims to identify the particular needs and knowledge gaps of the medically underserved, Spanish speaking migrant farm worker communities in South Florida, understand the role and potential impact of community health workers in supporting this populations access to breast cancer prevention interventions, and develop innovative methods to train community health workers to promote breast health and breast cancer early detection among this target population. Early Detection of breast cancer increases the chances for successful treatment and survival, decreases mortality rates, and lowers the overall cost of care.