Development of therapeutic molecules to inactivate the master transcription factor ISL1 in neuroblastoma
Progetto Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system that originates from neural crest cells. NB is highly heterogenous and clinical outcomes are significantly variable, ranging from spontaneous regression to an extremely aggressive behavior. In particular, metastatic NB is a cancer that kills the majority of the affected children. Although we have seen remarkable progress in cancer therapies, pediatric patients are still treated with highly toxic mixtures of chemicals and radiation, which cause important short and long-term side effects. Safer, innovative and targeted approaches for this aggressive form of childhood cancer are therefore urgently needed. In our laboratories, using public available data sets, we have performed an in silico preliminary analysis which revealed that the mRNA encoding the ISL-1 transcription factor is highly and specifically overexpressed in NB samples. ISL-1 is a transcription factor belonging to the LIM-homeodomain (LIM-HD) protein family which is essential for many developmental processes. In NB, ISL1 specifically interacts with the coactivator protein GATA3 and, together, they synergistically regulate the oncogenic pathways needed for progression and invasion of NB cells. Under this framework the engagement of the AURORA A/PI3 Kinase signaling axis has been recently shown.
In this project we propose to precisely define the role of collaborative ISL-1/GATA3 interaction in the context of neuroblastoma growth and progression, with the aim to develop a novel ISL1/GATA3 inhibitor endowed with antitumor activity. Specifically, we propose two strategies: i) design and development of peptides able to halt ISL-1/GATA3 oncogenic pathways in NB by interfering with the endogenous interaction of ISL1 with its coactivator GATA3; ii) selection and characterization of aptamers able to block ISL-1 DNA-binding domain (HD-ISL1) interaction with its DNA targets. Three research units, with complementary expertise, will collaborate to accomplish the following three specific research objectives:
Aim 1: Dissection of the molecular pathways and tumor cell properties affected by different tools for ISL1 inhibition
Aim 2: Design and characterization of ISL1 dominant negative peptides (ISL1beta)s
Aim 3: Selection and characterization of DNA/RNA aptamers blocking ISL1 activity.
The idea of interfering with the ISL1/GATA3 transcription machinery to control NB aggressiveness and spreading has emerged only very recently. Therefore, this project constitutes a first high risk/high gain proof-of-concept study that will address this issue. If successful, it will pave the way to a completely novel and promising strategy for targeted neuroblastoma treatment.