The V Foundation for Cancer Research Expands Executive Leadership Team
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V Foundation Grants
Quynh-Thu Le, M.D.
Funded by The V Foundation Wine Celebration
Daniel Wechsler, M.D.
Funded by the Apple Gold Group
The CALM-AF10 chromosomal abnormality is seen in aggressive pediatric and adult acute leukemias that have a poor prognosis. Our lab has discovered that CALM-AF10 interacts with CRM1, a protein that helps transport other proteins from the nucleus to the cytoplasm. This interaction is required to activate HOXA genes, which play a critical role in both CALM-AF10 and other leukemias. This discovery suggests that CRM1 may be important in other leukemias as well, as is significant because a new class of drugs that inhibit interaction with CRM1 (SINEs-Selective Inhibitors of Nuclear Export) has recently been developed. These drugs are effective in a number of human tumor types, and are currently in clinical trials for adult leukemias. Our studies indicate that SINEs may block cancer cells through an unappreciated and novel mechanism-inhibiting CRM1 involvement in activating HOXA genes. In this proposal, we will examine the molecular mechanisms by which CRM1 activates HOXA genes. We will then identify additional CRM1 target genes that are involved in causing leukemias. Studying this previously unrecognized role for CRM1 will enhance our understanding of how SINEs work, and provide preclinical support for their use in pediatric leukemia clinical trials. Since HOXA genes are involved in many hematopoietic malignancies (including MLL-fusion leukemias that are seen in 80% of infant leukemias), these studies may have broad implications for leukemogenesis.
Terry Badger, Ph.D., RN, PMHCNS-BC, FAAN
Funded by Hooters of America, LLC
The purpose of our study is to test psychosocial interventions to improve quality of life (QOL) (psychological, physical, social and spiritual well-being) for Latinas with breast cancer and their family members or friends who are helping them during their cancer journey. Latinas and their family members/friends often experience severe psychological distress during cancer treatment and this distress can negatively affect health and well-being. Participants in our study are assigned to either an 8-week supportive health education intervention or an 8-week telephone interpersonal counseling intervention. Both the health education and the counseling is provided over the telephone, and each person who participates in the study is called separately. Our trained health care workers call the women and their family members/friends at times that are convenient for them. Sessions are about 30 minutes on the phone each week for 8 weeks. Using the telephone to deliver this service removes many of the access barriers normally associated with counseling or health education. Participants can receive help in the privacy of their own homes over the telephone. In addition to participating in the 8 education or counseling sessions, we ask the women and their family members/friends to complete some questionnaires 4 times over the next 6 months to determine if the intervention was helpful to them. All study related materials, assessments and sessions are conducted in English or Spanish, depending on the person’s preference. At the end of our study, we also tell them about any other clinical trials that may be of interest.
Hatem Soliman, M.D.
Funded by Hooters of America, LLC
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.
Katherine Yeager, Ph.D., RN
Funded by Hooters of America, LLC
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.
Jedd Wolchok, M.D., Ph.D. & John Moral, M.D.
Funded in Collaboration With
Stand Up To Cancer (SU2C)
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.
Qing Zhang, Ph.D
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.
Ravindra Uppaluri, M.D., Ph.D.
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.
Alexander Guimaraes, M.D., Ph.D.
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.
