2010 Grants Funded
The following are current projects in which Stop Children’s Cancer is participating as we search for cures of cancers that affect children.
Purging of high-risk pediatric cancer cells from autologous stem cell transplant samples using myxoma virus
Eric Bartee, Ph.D., Postdoctoral Associate, Dept. Molecular Genetics & Microbioligy, College of Medicine, University of FL
Treatment of many pediatric cancers has progressed significantly in the last 30 years. However, some children with certain high-risk cancers, such as acute myeloid leukemia (ALM), relapsed/imatinib resistant acute lymphocytic leukemia (ALL) or neuroblastoma (NB), still display a poor prognosis. Procedures improving the treatment of these high-risk pediatric cancers would therefore be of great clinical benefit. Currently, one of the best treatment options for high-risk cancers is myeloablative chemotherapy combined with a hematopoietic stem cell transplant to rescue the patient’s immune system. Hematopoietic stem cells for transplant can come from three sources: cord blood, a HLA matched donor (allogenic transplant), or the patient’s own cells (autologous stem cell transplant, ASCT). All three sources have clinical issues. Cord blood is difficult to obtain in the quantities needed for stem cell transplantation, while allergenic samples can cause lethal graft-versus-host disease. In contrast, autologous transplant samples are easy to obtain and have no risk of graft-versus-host-disease; however, since these samples arise from the patient’s own blood or bone marrow they are frequently contaminated with cancer cells leading to an increased risk of disease relapse. The development of a technique to specifically remove these contaminating cells would greatly increase the safety and effectiveness of ASCT thus improving the treatment of children with high-risk cancers. Our lab has recently shown that an oncolytic virus called myxoma has the specific ability to eliminate cancerous AML cells contaminating adult ASCT samples prior to re-engraftment, thus limiting relapse. We believe that treatment with myxoma virus might also be able to remove contaminating cancer cells from children’s asct samples. This proposal will test the ability of maxima virus to infect and purge cancer cells derived from children with high-risk AML, NB, and ALL. The data generated in this proposal may lead to the use of a myxoma-based ASCT purging as a safe and effective treatment for children with high-risk cancers.
Identification of Novel Therapeutic Targets for the Treatment of Osteosarcoma
Padraic P. Levings, Ph.D. Post-doctoral Associate Department of Orthopaedics & Rehabilitation University of Florida College of Medicine
Osteosarcoma is the most common bone cancer in children. Even with chemotherapy and radical surgery frequently involving amputation, almost half of the children who develop osteosarcoma will die from it. One reason that chemotherapies often fail is they were developed with the thought that all cancer cells are the same. Recent findings, though, show that is not true. Within each tumor there are populations of “tumor-initiating cells” that are the most dangerous and have dramatically enhanced capacity to start new tumors and spread, or metastasize. Unfortunately these cells have been very difficult to identify and study. Recently, we have isolated tumor-initiating cells in osteosarcoma. Using recombinant DNA technology we developed a method that makes these virulent cells selectively glow green, unlike neighboring cells that are less malignant. When transplanted into mice these “green” cells show greater than 100-fold enhanced tumor initiating capacity. By comparing the genes that are active in the highly malignant (green) cells with those active in non-tumorigenic cells, we have identified the biological mechanisms supporting the differences in their behavior. The genes selectively active in the malignant cells enable them to bypass a key regulatory step in cell division, allowing them to divide very rapidly and metastasize. The genes expressed in the non-tumor forming cells indicate that these cells have stopped dividing in response to stressful conditions in the tumor and have shifted into a self-rescue and survival mode. This likely occurs because the osteosarcoma grows so rapidly that certain areas of the tumor become starved for oxygen and nutrients, which forces the cells to change their biology in order to stay alive. In the context of human disease, these cells are probably less of an immediate threat; however, since these cells are in “survival mode,” they have increased resistance to chemotherapeutic drugs and are likely responsible for local and distant tumor recurrence following treatment. For the present proposal we will work to extend these findings, with an eye toward the development of improved therapies for osteosarcoma. Our gene expression studies have allowed us to identify specific master regulatory genes (FOXM1, YY1, KLF4, and ID3) that are selectively active in each cell type. We hypothesize that by delivering inhibitory molecules that specifically block the activity of these genes we can: 1) stop rapid, uncontrolled cell division in the malignant cell population and thereby reduce their capacity to form tumors and metastasize; and 2) inhibit the capacity of the tumor cells to adapt to toxic growth conditions, prohibiting the emergence of quiescent, stress-resistant cell populations that may then later re-acquire malignancy. If our hypothesis is correct, the results of these studies will provide new understanding of the biology of osteosarcoma. They will also identify dramatically improved methods for therapeutic intervention that target the specific molecular pathways that enable growth and expansion of the diverse cell populations that comprise this dangerous form of cancer.
Characterization of a novel class of small-molecule Notch inhibitors
Lizi Wu, Ph.D., Assistant professor, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and T-cell ALL is an aggressive subset of ALL with poor clinical outcome. The genetic abnormality involving a gene called Notch1 cell surface receptor has been identified in more than 50% of T-ALL patients. Such abnormality results in the Notch signaling cascade that is constantly activated (“turned-on”) and this overactive signaling is sufficient to induce generation and progression of leukemia in animal models by promoting cell growth and survival. Therefore, the Notch signaling pathway is a promising therapeutic target in leukemia treatment. In this proposal, we will characterize a new class of small-molecule compounds from our high-throughput molecular docking screen, which are predicted to prevent aberrant Notch signaling and subsequent leukemia. These compounds have the potentials to be developed as targeted therapeutic agents for treating leukemia. Also, our studies will provide proof-of-principle that the Notch transcription complex is a promising target for new drug development.