Past Recipients - 2006

Baylor College of Medicine
Susan Blaney, M.D.
Patrick Thompson, M.D. (fellow)
Houston, TX

The most difficult to treat of the malignant brain tumors are gliomas - the majority of patients with malignant gliomas die within one year of diagnosis. Those that do survive often suffer life-long debilitating side-effects as a result of therapy. These side-effects can be particularly pronounced in young children because their brains are still undergoing development. This study will evaluate how effective nanoparticles (tiny gold particles) are in killing glioma cells in the "test tube" and how effective when injected into mice. Nanoparticles, in a cancer therapy application, are designed to absorb light and convert the energy to heat to kill tumor cells. If successful, the results of this study will lay the groundwork for testing new therapy in a clinical trial in humans.

Dana-Farber Cancer Institute
Aaron Foster, M.D.
Houston, TX

Cytotoxic T (CTL) cells are exquisitely sensitive and specific and can recognize and kill tumor cells while causing minimal damage to normal cells. In this study, a gene is inserted into the Cytotoxic T cells, that allows them to recognize GD2, a protein on the surface of neuroblastoma cells. Unfortunately, neuroblastoma cells do not produce the right molecules that CTL can detect so CTL are unable to find the tumor cells in the body. However, Dr. Foster's lab has discovered the unique molecule produced by neuroblastoma cells and knows the receptor molecules that recognize them. The hypothesis of this study is that if the genes for the receptor molecules are inserted into Cytotoxic T cells, they will then be able to seek out and destroy neuroblastoma cells. This hypothesis will first be tested in mice, and if successful a clinical trial will be planned.

Dana-Farber Cancer Institute
Charles W.M. Roberts, M.D.
Courtney G. Sansam, M.D. (fellow)
Boston, MA

Malignant Rhabdoid tumor is an aggressive and highly lethal cancer of early childhood which can occur in the kidneys, brain, face and other soft tissues throughout the body. Eighty per cent of affected children die within one year of diagnosis. The genetic cause of this disease has been identified as a specific inactivating mutation in both copies of SNF5. Their preliminary data shows that SNF5 may play a critical anti-cancer role by regulating key cellular processes, including cell cycle regulation, cell division, and DNA damage repair. Their ultimate goal is to determine how loss of SNF5 leads to the onset of tumor formation and also to identify new avenues for therapy against these lethal pediatric cancers.

Dana-Farber Cancer Institute
A. Thomas Look, M.D.
Jeong-Soo Lee, M.D. (fellow)
Boston, MA

Neuroblastoma is the most frequent extracranial solid tumor in children. Understanding of its molecular basis and significant advances in treatment still lag behind those achieved for other childhood malignancies. This study is trying to establish a new, innovative neuroblastoma animal model using zebrafish. The zebrafish nervous system is much like humans and they can contract the same types of cancers as we can. Also, their embryos develop ex-utero and are transparent allowing tissue development to be directly observed and accessibility for experimental manipulation. Furthermore, each female fish can generate hundreds of eggs each week, and in five days, those eggs rapidly develop. This study proposes to develop a transgenic zebrafish line that will misexpress a potent oncogene, MycN, in the nervous system and cause neuroblastoma. These optically clear embryos will allow the unprecedented direct visualization of tumorigenesis and the analysis of disease progression in real time. Thousands of offspring from the zebrafish neuroblastoma line can be easily collected and the long-term goal is to use them in mutagenesis and chemical studies to find genes and drugs that accelerate, or more importantly, suppress neuroblastoma.

Duke University Medical Center
Rob Wechsler-Reya, M.D.
Zeng-Jie Yang, M.D. (fellow)
Durham, NC

Medulloblastoma is the most common malignant brain tumor in children. Nearly half the children who develop medulloblastoma die from it, and survivors often develop severe side effects as a result of the treatment. Improved approaches to treating medulloblastoma are likely to come from a deeper understanding of the cellular and molecular basis of the disease. The studies in this proposal are aimed at identifying the cell of origin in medulloblastomas that result from mutations in the critical tumor suppressor gene patched. To determine whether these tumors arise from granule cell precursors or stem cells, we will eliminate patched in each of these cell types and determine whether this can promote medulloblastoma. Identifying this cell may allow us to develop more effective methods for eradicating the tumor.

Emory University School of Medicine
Muxiang Zhou, M.D.
Ningxi Zhu, M.D. (fellow)
Atlanta, GA

Neuroblastoma is the most common cancer in children. It is an aggressive type of tumor that occurs in nerve tissue and spreads rapidly to other areas of the body. Some patients with this cancer respond to treatment or recover spontaneously, while others are resistant to treatment and have a poor survival. Two proteins called MDM2 and XIAP have been discovered that appear to play important roles in the growth of pediatric and adult cancer cells. Many types of cancer cells that contain high levels of MDM2 and XIAP are resistant to therapy. The purpose of this proposal is to further study MDM2 and XIAP in neuroblastoma, to learn more about exactly how MDM2 regulates XIAP and how this affects cancer cell growth and resistance to drug therapy. In particular, Drs. Zhou and Zhu hope to increase the survival of those patients with tumors resistant to the drugs that are in use today.

Memorial Sloan-Kettering Cancer Center
David C. Lyden, M.D.
Rosandra Kaplan, M.D. (fellow)
New York, NY

Cancer is a proliferation of cells at a particular site but it is cancer's ability to spread and colonize other organs, which makes the disease so deadly. Metastasis, the spread and growth of cancer cells at distant locations from the primary site, is a complex, multi-step process that is not random. Certain tumors have a propensity to spread to specific organ sites. The work in this study is focused on the earliest steps in metastasis occurring at the distant site prior to the tumor cell arrival. Measurements developed in this study can help determine those patients more likely to have a tumor that will metastasize and form a useful schema for classifying patients for treatment based on this metastatic predisposition. The work will also investigate the earliest pathways in metastasis taking place at the distant site before primary tumor spread. Useful ways to target these pathways will likely provide new treatments to prevent cancer spread.

Stanford University
Michael Cleary, M.D.
Michaela Liedtke, M.D. (fellow)
Stanford, CA

Despite remarkable advances in the treatment of leukemia, the prognosis for certain subtypes remains poor. This particularly applies to leukemias that contain abnormalities of Mixed Lineage Leukemia (MLL) gene, which is responsible for 80% of infant leukemia, many secondary leukemias, and approximately 10% of overall acute leukemias in children and adults. Stanford University's laboratory originally discovered MLL, and has developed model systems to elucidate how MLL mutations cause leukemia. Recently, this lab discovered that a common MLL-fusion protein, called MLL-AF6, may impact Ras, an important signaling protein that can also cause leukemia. Drs. Cleary and Liedtke hypothesize that some MLL mutations may provide a double hit to activate both the MLL and Ras pathways, which act together to cause leukemia. Their study will test this hypothesis and refine the treatment of these poor prognosis diseases.

The Children's Hospital of Philadelphia
Stella T. Chou, M.D.
Philadelphia, PA

Children with Down Syndrome have a 500-fold increased risk of developing acute megakaryoblastic leukemia (AMKL). Recently, it was discovered that leukemic cells in Down Syndrome AMKL have mutations in GATA1, a gene important for the normal development of red blood cells and platelets. The work of this study will analyze GATA1 mutations in human samples, including those from Down Syndrome children to better understand the pathways by which Down Syndrome children develop leukemia. The goal is to ultimately contribute to improved diagnosis, treatment, and perhaps, even prevention.

The Children's Hospital of Philadelphia
Kelly Goldsmith, M.D.
Philadelphia, PA

Neuroblastoma, the most common solid tumor of childhood, is highly lethal. The treatment of high risk tumors is extremely toxic, including intensive chemoradiotherapy with stem cell transplant, and still only one-third of children survive. Chemotherapy works by causing cancer cells to die (undergo "apoptosis"), but many cancers, including neuroblastoma, have altered their apoptosis genes, making them resistant to these treatments. Dr. Goldsmith's lab has shown that peptides (small chains of amino acids) mimic the death activating (BH3) domain of BH3 proteins that can be used to kill neuroblastoma cell lines in cultures and in mice. However, peptides must avoid being degraded by cellular enzymes to be rendered useable as drugs. Dr. Goldsmith proposes to develop compounds for use in stabilizing these peptides for further use in neuroblastoma treatment.

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