Monday, March 31, 12:00 – 1:30 pm, in 489 Minor Hall

Retinoblastoma: Bridging Developmental Neurobiology and Cancer Genetics

presented by

Michael Dyer, Ph.D.
Member, Department of Developmental Neurobiology
HHMI Investigator
Head, Division of Developmental Biology
Co-Leader, Developmental Biology and Solid Tumor Program

Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. It is the third most common form of cancer in infants after leukemia and neuroblastoma. If left untreated, retinoblastoma is virtually always fatal, and even with the best treatment, the 10% survival rate for metastatic retinoblastoma is among the worst for any pediatric cancer. In the U.S., most patients survive because the cancer is detected early before it metastasizes, but saving the patient’s life often requires surgical enucleation. This is particularly debilitating for children with the most advanced form of bilateral retinoblastoma; approximately half of those patients lose at least 1 eye and are permanently vision impaired. The goal of our translational research is to identify new treatments to save the vision of children with retinoblastoma and the lives of children with metastatic progression. Retinoblastoma initiates with biallelic loss of the RB1 gene. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated RB1’s role in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. Here we show that the retinoblastoma genome is stable, but multiple cancer pathways can be epigenetically deregulated. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma.

 

Host: Marla Feller

 

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