Childhood Cancer

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Molecular Landscape for Targeted Therapy in Retinoblastoma

University of Miami
James Harbour, MD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Retinoblastoma is the most common pediatric eye cancer and one of the most important causes of pediatric cancer death worldwide. Almost all retinoblastomas are initiated by mutations in the RB1 tumor suppressor gene, yet these mutations do not explain why some retinoblastomas become highly lethal and others do not. Retinoblastomas are initially very oxygen-dependent, but with time they become resistant to low oxygen levels and become highly aggressive, leading to loss of the eye and metastasis. Recently, we discovered that in advanced retinoblastomas, there is a cluster of mutations that serve to activate a pathway that promotes cellular de-differentiation and metabolic adaptation to low oxygen levels in the central nervous system and retina. 

Project Goal
We hypothesize that retinoblastomas progress to become aggressive and life-threatening by acquiring mutations in this pathway and that more effective therapies for retinoblastoma can be developed by exploiting this molecular vulnerability in the cancer cells. To test this hypothesis, we propose the following specific aims: (1) Elucidate the mechanism of the pathway activation following RB1 loss; (2) determine the role of hypoxia in driving the pathway addiction in retinoblastoma cells, and (3) investigate the pathway inhibition as a therapeutic strategy in retinoblastoma cells. Our innovative experimental design will take advantage of our ability to generate retina-like “organoids” in culture using stem cell technology, and our collection of well-characterized low passage human retinoblastoma cell lines. The results of this project could break new ground in the development of novel targeted treatments for children with retinoblastoma.

Project Update - June 2, 2020
With the establishment of our stem cell-based retina in a dish platform, we’ve been able to study the early events in retinoblastoma (RB) tumor initiation. We have discovered a mechanism for self-regulation of progenitor cell amplification within the developing retina which goes awry upon the mutation of the RB1 gene and results in the uncoupling of differentiation and the rapid and uncontrolled proliferation of tumor cells. This has provided a promising new candidate target for therapy in RB, which we are evaluating using our iPSC-retinal organoid platform and in animal models of the disease.

Co-funded by: 
Tap Cancer Out