Research & Grants
2009 Grants Funded
Project Title:
Ethynyldeoxyuridine (EdU) as an antiproliferative agent in pediatric brain cancer
Principal Investigator:
Eric D. Laywell, Ph.D.
Assistant Professor
Department of Anatomy and Cell Biology
University of Florida College of Medicine
Lay Summary:
Primary brain tumors are the leading cause of cancer death from childhood cancer, with approximately 3,400 new cases being diagnosed each year. Of these pediatric cancers, glioblastoma multiforme (GBM) is one of the deadliest, with a survival rate of only 20-25% at five years. Thus, the identification of new and/or adjunctive therapies for the treatment of pediatric high grade gliomas is a high priority. Our work has recently shown that a brief administration of bromodeoxyuridine (BrdU), a thymidine analog employed for cell birthdating and measurement of proliferative index, results in a sustained and progressive suppression of cell division in neural progenitor and multiple cancer cell lines—a previously underappreciated effect that is independent from its known role as a radiosensitizer (Levkoff et al., 2008; Ross et al., 2008). A similar anti-proliferative effect is seen following administration of other thymidine analogs, iododeoxyuridine (IdU), chlorodeoxyuridine (CldU) and the new derivative, ethynyldeoxyuridine (EdU). However, the anti-proliferative effect seen following EdU administration is far more drastic. The focus of the current proposal stems from our findings that EdU administration dramatically slows the progression of a pediatric human GBM in an intracranial mouse model. For this proposal we will utilize this cell line to assess the efficacy of EdU treatment compared to, or in conjunction with, standard therapy. We will also assess the effect of EdU therapy on stem/progenitor cell pools. We hypothesize that the addition of EdU to standard therapy will result in an enhanced slowing of tumor progression over standard therapy alone. In addition, we predict that EdU therapy will briefly suppress stem/progenitor cell activity, but that these pools will recover due to the relatively slow, cyclical nature of indigenous stem cell proliferation.
Project Title:
Combination of Adenovirus type 12 E1A and HDACi as a Novel Strategy for Treating High-Risk Neuroblastomas: Molecular Rationale and In Vivo Anticancer Efficacy
Principal Investigator:
Daiqing Liao, Ph.D.
Associate Professor
Department of Anatomy and Cell Biology
UF Shands Cancer Center and
University of Florida College of Medicine
Lay Summary:
Neuroblastoma (NB) is one of the most common solid malignancies in children and remains the most lethal type of pediatric cancer, accounting for 15% of cancer deaths in children and adolescents. High-risk NBs with characteristics such as metastasis to distant organs and MYCN amplification are rarely curable, even with aggressive multimodal treatment strategies that are currently available. Clearly, innovative approaches are urgently needed for treating children with this disease. Despite devastating prognoses for patients with high-risk NBs, the overall incidence of this disease is relatively rare with only about 650 cases of new diagnoses each year in the United States. Consequently, there is a reduced market incentive for drug development in the pharmaceutical industry. Therefore, knowledge-based rational design of effective strategies in academic medical centers is of critical importance for identifying innovative therapies for children with this disease. NB cells are generally sensitive to genotoxic therapeutic agents that induce p53-mediated cell growth suppression and apoptosis. However, aggressive treatments with such agents can cause collateral DNA damage and devastating side effects that often confront survivors later in their life. Therefore, it is highly desirable to discover safer alternatives for treating NB. The inhibitors of histone deacetylases (HDACi) have emerged as a novel class of potent anticancer agents that show antineoplastic effects on NB cells in preclinical studies. However, these agents broadly impact epigenetic modifications and gene expression. Thus the observed cytoreductive effects by HDACi reflect net results of the expression of genes that are involved in both pro- and antiproliferation in tumor cells. HDACi-resistant cell populations eventually arise. Indeed, monotherapy using HDACi is often ineffective for treating diverse types of solid cancer. Thus, combinations of HDACi with conventional therapeutic modalities have been aggressively tested in multiple clinical trials of common malignancies. The activation of the pro-survival NF-?B pathway in tumor cells by HDACi has been suggested as a significant obstacle to the anticancer effects of HDACi. Therefore, agents that block NF-?B activation are expected to enhance clinical appeal of HDACi. As an outcome of a project currently funded by Stop! Children’s Cancer, we have unexpectedly found that adenovirus type 12 E1A (E1A) profoundly suppressed the growth of NB SH-SY5Y cells. It has been shown that Ad12 E1A effectively shuts down NF-?B activation. We also found that PXD101, a novel HDACi under multiple clinical trials, induced apoptosis in NB cells. We therefore hypothesize that E1A has potent anticancer effects and its combination with PXD101 might result in potential eradication of NB tumor cells. In this application, our objective is to test the anticancer effects of Ad12 E1A or PXD101 monotherapy and in combination with PXD101 in vitro and in vivo using a mouse xenograft model of NB. The innovation of this project rests on the original concept that E1A enhances the antitumor effects of HDACi through blocking the NF-B pathway and on a novel strategy based on the combination of HDACi and E1A for treating high-risk NBs. We expect that the results from this project will provide the proof-of-concept data of the proposed novel approach that might have clinical impact for treating children with highrisk NBs. The immediate impact of this pilot project is that the funding will allow us to produce compelling preliminary data that will be essential for securing long-term funding from NIH and DoD to establish a research program at UF dedicated to finding cures for a deadly type of pediatric cancer.
Project Title:
Combination of adeno-associated viral vector and cell-specific aptamers as a novel gene therapy strategy for childhood acute lymphoblastic leukemia
Principal Investigator:
Shoudong Li, Ph.D.
Postdoctoral Associate
Department of Molecular Genetics and Microbiology
University of Florida College of Medicine
Lay Summary:
Acute lymphoblastic leukemia (ALL), a group of malignant disorders of lymphoid progenitor cells, is the most common cancer in children. Although current therapies cure most children, about 20% of patients fail treatments. Therefore, new therapeutic strategies are needed to improve the cure rate for childhood ALL. The present proposal attempts to develop a novel gene therapy strategy for ALL treatment by combination of recombinant adeno-associated viral (rAAV) vector technology and aptamer technology. AAV is a safe gene delivery vector as wild-type AAV does not cause any disease. Importantly, AAV vectors can initiate long-term expression of transgene in transduced cells. Aptamers are single-stranded DNA (ssDNA), RNA, or modified nucleic acids that have the ability to bind specifically to target molecules ranging in size from small organics to proteins. A research group at the University of Florida recently isolated aptamers that specifically recognize not only cultured ALL cell lines but also ALL cells from clinical samples. We hypothesize that some cell-specific aptamers, if conjugated to AAV particles carrying therapeutic genes for ALL, can guide the AVV to get into ALL cells. Expression of therapeutic genes, such as pro-apoptotic genes and immune-stimulatory genes, from AVV in targeted ALL cells in patients may induce cancer cell death or lead to enhanced anti-cancer immunity. In the proposal, we will develop an aptamer-AAV gene delivery system in vitro using a T-cell ALL cell line, CCRF-CEM. This may provide a model for development of new gene therapy strategy for treatments of childhood ALL and other cancers in children.
STOP! Children's Cancer, Inc. Medical Advisory Board
|
David F. Muir, Ph.D., Chairman Alan P. Fields, Ph.D. C. Parker Gibbs W. Stratford May, Jr. MD, Ph.D. |
William B. Slayton, M.D. Stephen Sugrue, Ph.D. Margaret Wallace, Ph.D. |
