Biography

A. Thomas Look, M.D., is a Professor of Pediatrics at Harvard Medical School and a member of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute.  Look received his M.D. degree and postgraduate training in Pediatrics from the University of Michigan and his fellowship training in Pediatric Oncology at St. Jude Children’s Research Hospital, where he advanced over twenty years to become Chair of the Experimental Oncology Department and Professor of Pediatrics at the University of Tennessee College of Medicine. He moved from St. Jude Children’s Research Hospital to Dana-Farber Cancer Institute and Harvard Medical School in 1999 specifically to establish a research program in the zebrafish as a model of human cancer. 

Over the past four decades, Look has published 394 peer-reviewed papers addressing the molecular basis of malignant transformation, aberrant proliferation and apoptosis in cancer cells and the application of molecular genetic findings to improve the treatment of malignancies of children and adults, particularly T-cell acute leukemia, neuroblastoma and myelodysplastic syndrome. 

Abstract

High-risk neuroblastoma accounts for about 15% of childhood cancer deaths and arises from precursors of the peripheral sympathetic nervous system. Retinoids are clinically used to inhibit growth of neuroblastoma cells through reconfiguration of the regulatory enhancer landscape. Its effects, however, are completely reversible after drug withdrawal, leading to rapid tumor cell proliferation. Here, we sought to identify epigenetic modifiers that potentiate the antiproliferative effects of retinoids in neuroblastoma. We identified PF-9363, an inhibitor of the histone H3K23 acetyltransferases KAT6A/B, as synergistically inhibiting neuroblastoma growth in combination with retinoids. PF-9363 plus retinoids induces durable growth arrest, which persists beyond retinoid withdrawal in vitro and in vivo with sustained Polycomb-mediated repression of oncogenic transcription factors MYCN, PHOX2B and GATA3. Moreover, PF-9363 plus retinoids increases GD2 expression, rendering neuroblastoma cells more sensitive to anti-GD2 immunotherapy. Overall, our studies demonstrate that KAT6A/B inhibition increases the effectiveness of retinoids and GD2-targeted immunotherapy in neuroblastoma.