Characterization of MYCN effects in retinoblastoma progression and targeting MYCN for personalized retinoblastoma treatment (MYtargetRB)

• Applicant: Professor Dr. Alexander Schramm, since 12/2019
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388505170

Retinoblastoma is the most common eye tumor in childhood. It is the paradigm of a tumor that is initiated by biallelic inactivation of the tumor suppressor gene RB1. Additional genetic alterations are rare, but amplification of the transcription factor MYCN is common and MYCN mRNA expression exceeds levels observed in other tumor entities. Addressing MYCN deregulation is considered a promising therapeutic approach across entities. In MYtargetRB, we hypothesize that a more complete understanding of the functional consequences and molecular mechanisms of MYCN modulation in retinoblastoma will define a patient target group who may benefit from MYCN-directed therapies. Our experimental approaches include genetic targeting of MYCN expression in retinoblastoma cell lines using MYCN-directed shRNA to characterize the effect of MYCN on proliferation, apoptosis, cell cycle, tumor cell invasiveness and metastatic potential in vitro and in in ovo assays. The second part of MYtargetRB is dedicated to investigate the potential of MYCN as a candidate for innovative targeted therapies of retinoblastoma. Preliminary results show an encouraging anti-tumor effect targeting either epigenetic regulation of MYCN or the stability of MYCN protein. The effect of several small molecules targeting MYCN will be assessed in in vitro and in ovo retinoblastoma models and the effect on gene expression of downstream targets will be quantified with RNA-Seq. Based on the characteristics in gene expression profiles, we will define a MYCN signature as a predictive biomarker capable of selecting the molecular tumor subgroup that best responds to MYCN directed therapies. This signature serves to then classify twelve primary retinoblastomas and to define the clinical parameters of each subgroup. The main goal of this project is to characterize the role of MYCN in retinoblastoma tumorigenesis and to provide first data for the therapeutic potential of MYCN targeting in retinoblastoma. A new therapeutic agent is needed to improve survival rates in patients with the devastating prognosis of metastasized retinoblastoma and to reduce long-term sequelae in survivors.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Professorin Dr. Petra Ketteler, until 12/2019