Shizhen (Jane) Zhu, M.D., Ph.D.

Funded by the Dick Vitale Gala in honor of Leah Still

Neuroblastoma, an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS), accounts for ~10% of cancer-related deaths in childhood. About half of all patients, especially those over 18 months of age with amplified copies of the MYCN oncogene, present with evidence of widespread metastasis at diagnosis and have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy. Attempts to improve the treatment of metastatic neuroblastoma have been slowed by the lack of a full understanding of the multistep cellular and molecular pathogenesis of this complex tumor. Recently, I developed the first zebrafish model of neuroblastoma metastasis by overexpressing two oncogenes, human MYCN, which is amplified in 20% of neuroblastoma cases, and mutationally activated SHP2, which is the second most frequently mutated gene in high-risk neuroblastoma. This transgenic model affords unique opportunities to study the molecular basis of neuroblastoma metastasis in vivo, and to identify novel genes and pathways that cooperate with MYCN and activated SHP2 to promote this usually fatal stage of disease development. This research approach is expected to reveal novel molecular targets that can be exploited therapeutically. To achieve this goal, I propose to establish reliable in vivo zebrafish models of the aberrant genes and pathways that contribute to neuroblastoma metastasis. In the near future, these models will be used to screen for effective small molecule inhibitors that block specific steps in metastasis with only minimal toxicity to normal tissues, and thus would be assigned high priority as candidate therapeutic agents.

Branden Moriarity, Ph.D.

Funded by the Dick Vitale Gala in memory of Dillon Simmons

Cancer is a disease genetic in origin and a major cancer causing gene is MYC. Many human cancers, including pediatric sarcomas such as osteosarcoma, rhabdomyosarcoma, Ewing’s, and synovial sarcoma, are driven by MYC. It has been argued a major leap towards finding a cure for these cancers will be the development of therapies that target MYC. Unfortunately, MYC has been notoriously challenging to target therapeutically. We have recently found a new regulator of MYC called PVT1. We demonstrated PVT1 helps sustain MYC at elevated levels in adult cancer cells, and when PVT1 is removed MYC returns to levels seen in non-cancer cells. This reduction in MYC drastically reduces the cancerous potential of these cells. Thus, the purpose of this work is to investigate this phenomenon in pediatric sarcomas. We have preliminary demonstrating this interaction indeed occurs in pediatric osteosarcoma cancer cells and removing PVT1 leads to reduced MYC levels; which we previously demonstrated leads to diminishes growth and viability of cancer cells. Accordingly, this work will investigate if this phenomenon occurs in many pediatric sarcomas and develop a therapeutic approach to inhibit PVT1 in pediatric cancer patient tumors, leading to loss of MYC and regression of tumors. This would be a breakthrough for the treatment of pediatric sarcoma as this disease has seen little to no advances in targeted therapy over the last several decades. If an effective therapeutic is developed, a clinical trial using this therapeutic approach will be carried out in pediatric sarcoma patients in the future.

Jamie Bakkum-Gamez, M.D.

Uterine cancer is a cancer that grows in the lining of a woman’s uterus (womb). In the United States, uterine cancer is the most common cancer of the female sex organs. Most often, women with this type of cancer have periods that are not normal or have bleeding after they have gone through menopause. By the time this bleeding starts, the cancer may have spread to other sites and organs. If it is caught at an early stage, it can be treated more easily and there is a higher chance of cancer cure. Right now there is not a screening test for this cancer. Our research project aims to design a simple screening test for uterine cancer.

Uterine cancer is caused by changes in the normal cells lining it. These changes can be found in the blood and fluid that passes into the vagina from the uterus. This fluid can be collected using a tampon. Better understanding changes in normal sex organ tissues and in different types of uterine cancer will help us identify the changes that truly represent the presence of a cancer. Our screening test will find the changes that identify cancer in fluid that can be collected using a tampon. We also expect that the cancer changes will be found even in women without bleeding that have an early cancer. The hope is that finding cancer early will lead to improved cancer outcomes.

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