Dr. Hatem Soliman, a researcher and breast cancer medical oncologist at Moffitt Cancer Center, will be conducting a project to help increase accrual to clinical trials for breast cancer patients. The aim of the project is to first assess patient awareness of cancer clinical trials, perceived barriers that may prevent participation and what information would help patients to more readily participate in trials. Information will be collected from a target of 100 Moffitt breast cancer patients. Once this initial assessment is completed, the second aim of the project is to use this information to create a web hosted video to address questions and issues identified through the survey as perceived barriers to breast cancer clinical trial participation and provide vital information that may help increase participation. A short post video survey will be administered to ascertain the impact of the information presented on increasing clinical trial participation. If successful, our ultimate goal would be to expand this methodology to other cancer types to help increase clinical trial participation.
Cancer clinical trials provide much of the evidence for clinical guidelines and standards of care. All patients should have access to the latest treatments and the high quality care that typifies clinical trials. Unfortunately, a small percentage of patients enroll in cancer clinical trials, especially minorities. The purpose of this project is to develop and test an easy to understand culturally informed video with a racially diverse group of breast cancer patients and assess the effect of the video on clinical trial enrollment. This video, which will be easily accessed via smart phones, tablets, and computers, will provide standardized communication between the patient and healthcare provider and will address benefits and barriers through patient and physician stories. The setting for this project is Winship Cancer Institute, Georgia’s only cancer center designated by the National Cancer Institute. Our multidisciplinary research team will complete this study through the following four step process: 1) form a Community Advisory Board composed of individuals diagnosed with breast cancer to provide input 2) establish a tracking method to identify potential breast cancer clinical trials participants; 3) develop the video; and 4) pilot test the video. Simple, effective interventions are needed to support the cancer clinical trials enrollment process. This multi-disciplinary effort is a first step to provide educational programs to a diverse group of patients with the end goal of increasing enrollment rates. Results of this study will inform future educational programs and can be adapted to other minority groups.
Pancreatic cancer is a lethal disease. 95% of patients die within 5 years of diagnosis, despite our best current treatments including surgery, chemotherapy, and radiation. By 2020, pancreatic cancer is projected to become the second leading cause of cancer death in the United States. Novel strategies to combat this deadly disease are urgently needed.
T-cells are highly specialized cells of the immune system designed to protect the human body from infections and cancer. In the past decade, we have discovered that T-cells recognize proteins that only cancers make, identifying cancers as foreign, triggering T-cells to kill cancers. Cancers however are equipped with strategies to escape T-cells. Our group has recently identified a drug paricalcitol that eliminates barriers that tumors have developed to block T-cell attack. Our preliminary findings demonstrate that this drug increases T-cell numbers within tumors by greater than 10 fold. These results are promising as it allows us to further boost T-cells with other drugs, and increase the ability of T-cells to kill tumors.
Our proposed research will delve deep into understanding the specific proteins on tumors that T-cell recognize, the specifics of how tumors create barriers to block T-cells, and combining paricalcitol with other drugs that boost T-cells in a clinical trial. Our proposals allow us to gain a deeper understanding of the biology of T-cells in pancreatic tumors so that we may develop better treatments to improve outcomes in patients.
Triple Negative Breast Cancer (TNBC) accounts for 15-25% of breast cancers. TNBC is well known for its aggressive clinical behavior and early peak of recurrence. Due to the lack of good therapeutic targets, TNBC represents the specific subtype of breast cancer with worst prognosis. Therefore, there remains the urgent question to be addressed: Can we identity important biological features that serve as high value targets for the development of novel treatment modalities for TNBC? This line of research carries significant social and economic importance. Hypoxia is a characteristic of solid tumor, which contributes to radiation and chemotherapy resistance. One important feature of tumor cells is that they sense the oxygen tension and rewire their signaling pathway to survive under harsh living conditions. EglN2 prolyl hydroxylase serves as an important oxygen sensor. In this proposal, we presented some preliminary data in the TNBC cell lines that getting rid of EglN2 could decrease TNBC tumor growth and invasion. We propose to obtain primary tumors from TNBC patients, implant them into mice and treat them with siRNA nanoparticles that deplete EglN2, which will be used to test the efficacy of targeting EglN2 in a patient relevant system. In addition, we will study mechanistically how EglN2 protein stability is regulated by FBW7 E3 ligase complex. Furthermore, we will implement a novel screening for EglN2 specific inhibitors, which will motivate testing the effect of these potential inhibitors on TNBC tumorigenesis. Successful completion of proposed research will open new therapeutic avenues in treating TNBC.
One of the most exciting frontiers in cancer treatment is the field of immunotherapy where beneficial effects have been observed in a broad range of cancers. The major goal of our project is to identify the determinants of immunotherapy success in patients with head and neck cancers. We are performing a novel clinical trial with an immunotherapy-targeted agent that allows the patient’s own immune system to control their cancer. Using samples from this trial, our goal is to understand why some patients do or do not respond to immunotherapy. We have assembled a multi-disciplinary team that will use genetic and immunologic tests on patient samples to clarify which patients may actually benefit from this powerful approach. These data will allow us to define a precision approach to immunotherapy and in addition will provide an improved biologic understanding of the mechanism of immunotherapeutic modalities.
The poor survival of pancreatic adenocarcinoma (PDAC) patients is due partly to diagnosis at late-stages, concomitant with relatively ineffective cytotoxic therapies. This poor chemotherapeutic response may relate to unique properties of the PDAC tumor microenvironment (e.g. poor perfusion, increased fibrous stroma), which may be a barrier to drug delivery. We hypothesize a link between tumor stroma and microvasculature and have developed a steady-state MRI method that quantifies microvascular imaging biomarkers to study PDAC, using long-lived FDA-approved intravascular magnetic nanoparticles (MNP). By applying these techniques to angiotensin receptor-blockade, which directly effects fibrous stroma, we have demonstrated sensitivity to vascular normalization, a direct correlation with histologic assays, and improved drug delivery as measured by 18F-5 fluorouracil (5FU) positron emission tomography (PET). Based on exciting results from the Coussens, Varner, Bar-Sagi and Simon laboratories indicating that B cell-regulated pathways foster PDAC progression, and two reports from the Levy and Soucek laboratories, indicating that therapeutic targeting of Bruton’s tyrosine kinase (BTK) reprograms the immune microenvironment in PDAC to normalize vasculature and mobilize CD8+ T cells resulting in improve efficacy of gemcitabine (Gem) chemotherapy, we propose to quantitatively evaluate microvascular changes following BTK inhibition. These provocative preclinical data are now being translated to the clinic in a funded (Stand-Up-2-Cancer (SU2C) Phase 2 trial). The goal of this proposal, therefore, is to test the hypothesis that MRI measures of tumor microvasculature using MNP are surrogate biomarkers of therapeutic response to BTK inhibition by validating in mouse models and translating in humans participating in this SU2C trial.
Funded by the Dick Vitale Gala in memory of Lauren Hill
We have recently demonstrated that neuronal activity in the cerebral cortex can drive the growth of deadly brain tumors called high-grade gliomas. High-grade gliomas include tumors that affect children, teens and adults, such as glioblastoma, anaplastic oligodendroglioma and the childhood tumor diffuse intrinsic pontine glioma (DIPG). High-grade gliomas are the most lethal of all brain tumors. An important way that brain activity promotes the growth of these brain tumors is through release of a molecule called “neuroligin-3”. The purpose of this project is to develop a new therapy for these deadly brain cancers designed to sequester neuroligin-3 like a molecular sponge. We have shown that such a strategy is effective in principle, and now seek to test and optimize this strategy in preclinical models of high-grade glioma.
Research has advanced new anticancer drug therapies, saving many lives, but it is estimated that cancers will still kill more than half a million Americans specifically African and Hispanic Americans. New, safe and effective treatment approaches are urgently needed. Especially promising are treatments including cancer cells, through a large family of proteins called “T cell receptors” (AKA TCRs) which bind particular molecules associated with tumors Dr. Chapuis is an expert in identifying tumor antigens, genetically engineering matching TCRs, putting them in T cells and then infusing these enhanced methods to develop new engineered T cell therapies for patients for whom best available therapies are simply inadequate. For patients with non-leukemia patients, further optimizing methods that can also be used to target other antigens in tumors where WT1 is not expressed. She also proposes therapy after the safety of each is established for a broader future impact, including for other patients with urgent needs.
Ovarian cancer is a devastating disease heightened by its tendency to present when metastatic disease is already present. Many women diagnosed with the disease complain that despite their best surveillance efforts, the disease occurred completely “under the radar.” While most women are symptomatic at diagnosis, the symptoms are veiled as common inconveniences of daily life, such as bloating, fullness and pelvic discomfort. Primary treatment involves a combination of surgery and chemotherapy. Tumor control is achieved in >75%. However, despite these early treatment gains, a typical patient will suffer recurrence within 2 years, where limited curative options exist. These clinical observations have fueled the search for better treatment agents and strategies. The unprecedented explosion of information arising from analyses of the cancer cell environment has directed new investigative opportunities. One such observation in line with this clinical story is the efficacy of agents that target new blood vessel formation. Several clinical trials with these agents in both initial and recurrent disease settings have demonstrated benefit to women. However, improvement in survival has not been realized. Our investigation into why this might occur has uncovered that the immune system may be adversely contributing. Of great concern, though, is that this process appears to be induced by the very drug being used for therapy. The current proposal tackles this issue by specifically investigating and targeting these immune cells. Our clinical trial design uniquely identifies patients where this “escape” effect may be at work. The translationally-rich proposal holds promise to substantially improve treatment outcomes.
Neuroblastoma is the most common extracranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs commonly in high-risk neuroblastoma and marks a particularly aggressive and lethal form of the disease. We and others have described an array of highly targeted inhibitors to block kinases both upstream and downstream of MYCN in neuroblastoma. Among these targeted inhibitors, we have recently described a novel conformation disrupting inhibitor of Aurora Kinase A which potently induces MYCN degradation through an allosteric change in Aurora Kinase A. Because these inhibitors target distinct members of the MYCN pathway, we hypothesize that they will have nonoverlapping toxicities and that combinations of MYCN targeted therapies will more potently block MYCN. In Aim 1 of this proposal we will rigorously test combinations of MYCN targeted therapies for pre-clinical efficacy with the goal of rapidly translating combinations into patients with neuroblastoma. In Aim 2 of this proposal we will develop our novel conformation disrupting Aurora Kinase inhibitor to “dial out” toxic Aurora Kinase A activity and finesse more potent MYCN degradation in neuroblastoma to optimize therapeutic efficacy. Successful completion of this proposal will result in direct and rapid translation of therapeutic combinations of MYCN targeted therapies into children with neuroblastoma and provide new clinical grade drug candidates for conformation disrupting Aurora Kinase A inhibitors.
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