Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
Funded by the Dick Vitale Gala with a gift from Derek and Christin Thompson in memory of Bryan Lindstrom
Bone marrow failure syndromes are a collection of disorders characterized by inadequate production of blood cell lineages from a common progenitor, the hematopoietic stem cell. Dyskeratosis congenita is an inherited bone marrow failure syndrome that comes to clinical attention during early childhood, and is associated with high rates of malignancy in children and young adults, with cancer being a major cause of death in patients. DNA sequencing efforts have established that dyskeratosis congenita has a clear genetic determinant, with patients carrying mutations in their DNA that affect the function of telomerase, a dedicated protein complex that is primarily responsible for maintaining the structure of our chromosomes.
Research regarding dyskeratosis congenita has been hampered by a lack of adequate models. In this proposal we are using genetically engineered human pluripotent stem cells to precisely determine the role that TERC, one of the main components of the telomerase complex, plays in bone marrow failure and cancer in children afflicted with dyskeratosis congenita. Using our innovative model, we will understand the importance of TERC for stem cell regulation and blood development. Recently we developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type present in the circulatory system. This allows us to reproduce the clinical effect of this disease, in a tissue culture dish, and therefore precisely understand the disease progression in dyskeratosis congenita. Our goal is to help delineate novel treatment strategies against dyskeratosis congenita, a condition that currently has no cure.
Acute myeloid leukemia (AML) is a devastating disease with poor survival. The standard treatments of chemotherapy and/or stem cell transplantation are not specific, and are toxic to blood cells, resulting in severe treatment-related complications for patients. Leukemias are composed of rapidly dividing “blast” cells, and the more rare “leukemic stem cells” (LSCs). These LSCs can lead to resistance and relapse, because they can evade chemotherapy. To achieve long-term remissions in AML and prevent relapse, we need to find more specific ways to kill LSCs.
The enzyme PI3 kinase (PI3K), which can modify proteins inside the cell, is more active in leukemic cells than in normal cells. However, PI3K is also important in normal blood cells. We identified a strategy to specifically kill leukemic cells by blocking specific components of PI3K called “isoforms”, which can sometimes substitute for each other in normal blood cells. We will determine whether this therapeutic strategy can also be used to kill LSCs.
Leukemic cells can also evade chemotherapy by hiding in their bone marrow microenvironment, the “niche”. Niche cells and leukemic cells “talk” to each other by sending signals back and forth, which can protect leukemic cells from chemotherapy. Cells need PI3K to process such signals. Inhibition of PI3K in niche cells could potentially kill leukemic cells by short-circuiting this crosstalk with the niche. We have found that PI3K in the niche cells is important for blood development. We will now examine whether inhibition of PI3K in the niche can compromise leukemic growth and progression.
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.
2015 V Foundation Wine Celebration Vintner Grant in Honor of Rick and Elaine Jones With Support From Becky and Howard Young
Pancreatic cancer is an almost universally deadly disease because it spreads quickly to other organs (metastasizes) easily and there is no early detection mechanism. Surgery can be an effective treatment, but less than 10% of patients are diagnosed at a resectable stage. About 30% of patients with pancreatic cancer have locally advanced pancreatic cancer, where the cancer has not yet metastasized, but cannot be removed by surgery. The only way to kill locally advanced pancreatic cancer is with chemotherapy and radiation. Radiation therapy can kill any tumor but its therapeutic effects are limited by unavoidable damage to normal tissue near the cancerous target. For instance, adenocarcinomas of the pancreatic head require high doses of radiation to achieve tumor control, but these cannot be safely given to patient because the pancreas sits near a part of the small bowel called the duodenum, which is very sensitive to radiation damage. Thus, we can never give the amount of radiation needed to kill the tumor without causing undue harm to the duodenum (and the patient). My research will solve this problem by strengthening the duodenum and nearby tissues to withstand higher doses of radiation by activating the hypoxia-inducible factors (HIFs), which promote recovery from radiation treatments without protecting tumors. My published work has shown that HIF2 can reduce GI toxicity from radiation, and this proposal seeks to use this biology to make the duodenum more resistant to radiation toxicity to allow us to give higher doses of therapeutic radiation to the pancreatic tumors.
Pancreatic cancer is a devastating disease. Current therapies for pancreatic cancer have modest effects as the 5-year overall survival is a discouraging 5-6%. One contributing factor to increased morbidity and mortality is cancer cachexia. Cachexia is defined as weight loss, muscle atrophy, fatigue, and weakness, in someone who is not actively trying to lose weight. Cachexia is a devastating condition affecting most cancer patients, but significantly more pronounced in patients with pancreatic cancer and is a significant therapeutic and personal dilemma. I have a significant background in clinical oncology with specialization in pancreatic cancer. The aims of my therapies are to improve and extend my patient’s quality of life. Unfortunately, our therapies can be premature or delayed primarily by the overall health of my patients. Premature in that we treat weak and malnourished patients that should not be given aggressive therapies for the risk of causing more harm than good. Delayed in that the patient is too weak and malnourished to receive any therapy and therefore will succumb earlier to their disease. With the expertise and passion of our collaborative group, we will investigate the possible biologic factors that contribute to pancreatic cancer cachexia. Our plan will be the future development of strategies to interfere with its deleterious effects on our patient population. In summary, we hope to improve the quantity of quality life in patients with pancreatic cancer.
About 1 in 8 U.S. women will develop breast cancer over the course of her lifetime, and in the year of 2014, breast cancer has claimed the lives of approximately 40,000 women and men in the United States. Although initial remission can be achieved with chemo-treatments, the worry and fear of treatment resistance, recurrence, and death still have a deep impact on many breast cancer patients. It is recognized that cancer stem cells (CSCs), a long-lived, self-perpetuating cell population that can infinitely give rise to the bulk of a tumor as the “seed” of the cancer, account for cancer initiation, progression, chemoresistance, and recurrence. To date, treatment strategies designed to eliminate the genesis of the cancer (CSC) still remain a significant challenge. This project aims to identify critical cell components and their working mechanisms that are used to sustain the stemness of breast CSCs, and the identified mechanism will further be therapeutically targeted to direct CSCs to a differentiated cell (non-stem cell) fate, allowing breast tumors to become terminally dormant and sensitive towards chemotherapy. Our goal is to eradicate breast cancer in the next 10 years, and with the common stemness properties of CSCs between many cancer types, we believe that the applications generated from our research will continuingly contribute to overcoming the therapeutic hurdles of a broad spectrum of cancers and significantly benefit the cancer patient and the survivor community for decades.
Rectal cancer affects 40,000 individuals in the US every year. The primary treatment is surgical resection when possible but a growing number of patients receive pre-operative chemo-radiation therapy before surgery to improve outcomes. In up to 30% of these patients, the tissue removed from the rectum after chemo-radiation is found to have no evidence of the original tumor. However, at present, the only accurate way to find out if the tumor responded completely to pre-operative chemo-radiation is to go through with surgery. There are no established biomarkers that can identify patients with complete response before surgery so that they may be potentially saved from a morbid operation. In previous work, we have shown that cancer mutations can be detected in blood plasma from advanced cancer patients. We have also shown that changes in the circulating levels of these mutations correlate with tumor burden. In this project, we are evaluating detection of cancer mutations in plasma from patients with rectal cancer as a potential biomarker. Our goal is to identify patients with rectal cancer whose tumors have completely receded after completing chemo-radiation before they under go surgery. These results will set the stage for prospective follow-up studies to enable biomarker-guided non-operative management of localized rectal cancers.
In spite of tremendous advances in the treatment of estrogen receptor-positive (ER+) breast cancer using therapies directed against the estrogen receptor (ER), patients frequently develop resistance to these therapies. These resistant tumors remain the most common cause of breast cancer death, yet mechanisms by which this resistance develops are poorly understood. Much more work is required to fully understand all of the clinically relevant resistance mechanisms in breast cancer patients treated with ER-directed therapies. Moreover, there is an urgent need to develop new therapies for patients who no longer respond to these therapies. The goal of this project is to improve our understanding of resistant ER+ breast cancer by using cutting-edge genomic technology to directly characterize tumor samples from patients who have developed resistant breast cancer, as well as systematic pre-clinical approaches in breast cancer cell lines. First, we will use next-generation sequencing technology to comprehensively characterize the genomic and molecular alterations from breast tumor samples obtained from 50 patients who have developed resistance to the drug fulvestrant, an FDA-approved therapy that directly targets the estrogen receptor. At the same time, we will conduct a systematic pre-clinical study in breast cancer cell lines to identify genes that might contribute to resistance to fulvestrant. Once completed, this work should help us understand how ER+ breast cancers develop resistance to ER-targeted therapies, as well as identify new targets and therapeutic strategies in resistant breast cancer.
Brain cancer is the leading cause of cancer-related death in children. Current therapies for medulloblastoma, the most common type of aggressive childhood brain cancer, cure 60-80% of patients from their disease, however, these treatments are non-specific, highly toxic, and impose devastating consequences on the developing child. Novel, rationally designed therapies informed by studying medulloblastoma in the laboratory and identifying the causes of this childhood cancer are desperately needed to improve patient outcome and quality of life for survivors and their families.
Studies outlined in this application aim to gain a better understanding of the genes responsible for a large subset of medulloblastoma patients whom are typically associated with an exceedingly poor clinical outcome. There are currently no effective therapies designed to specifically treat these high-risk patients and as such they are treated with standard protocols that carry with them considerable side-effects, effectively stealing any possibility of a normal ‘life after cancer’ for kids fortunate enough to survive.
Discoveries made using state-of-the-art technologies during my recent Post-Doctoral Fellowship revealed important new insight into the genes involved in these high-risk medulloblastoma patients. The most compelling evidence from my analyses implicated a new gene – KBTBD4 – a gene not previously implicated in childhood brain cancer, nor in any other cancer type. The experiments outlined in this application will directly evaluate the role of this novel, frequently altered gene (most commonly affected gene in high-risk patients) in medulloblastoma and establish its potential as a future target of therapeutic intervention in high-risk patients.
Lung cancer is the most common cause of cancer death in the US and worldwide. Because it has a five-year survival rate of only 18 percent, new therapeutic approaches are urgently needed. We propose to develop novel therapies by targeting the Wnt signaling pathway, which is involved in normal cell growth, but is also implicated in lung cancer development, progression and metastasis. Historically, Wnt signaling has been challenging to target directly, but epigenetic changes that chemically modify DNA or DNA packaging proteins, known as histones, can turn Wnt signaling on or off. In over 80% of lung cancers, the WIF1 protein that normally turns Wnt signaling off, is not produced. We showed that a drug which alters specific modifications to histone 3 restores the production of WIF1, shuts down Wnt expression and induces lung cancer cell death. To advance our observations from bench to bedside, we will 1) determine how specific histone modifications and changes to WIF1 production and Wnt signaling correlate with the disease and its clinical outcomes; 2) analyze the biochemical mechanisms that alter histone modifications to suppress Wnt signaling; and 3) test the effectiveness of two experimental drugs that alter histone modifications to inhibit the tumorigenesis and progression of human lung cancer transplants in mouse models. Successful completion of these studies are expected to unravel important epigenetic pathways that promote Wnt signaling to induce lung cancer, and to identify new drug targets that will suppress Wnt signaling and dramatically improve the outcomes for lung cancer patients.
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