Interdisciplinary Thesis Project in BIO-ORGANIC CHEMISTRY for the development of novel compounds to treat GLIOBLASTOMA MULTIFORME
Bachelor or master students in biotechnology 
Thursday 03 October 2019

In the context of a collaboration between the Laboratory of Translational Genomics led by professor Alessandro Quattrone (CIBIO Department) and professor Ines Mancini (Laboratory of Bio-Organic Chemistry, Physics Department), we search for a motivated student interested in a bachelor or master thesis project regarding the development of compounds with application in the treatment of glioblastoma multiforme, the most common and lethal primary brain tumor in the adult.

In particular, the project is focused on the organic synthesis, purification and structural characterization of derivatives of a lead compound previously identified. The efficacy of the synthesized derivatives will be then tested in vitro using glioblastoma stem cells.

The interested person will carry out synthetic sequences and will learn the use of purification and structural characterization methods (Nuclear Magnetic Resonance, Mass Spectrometry, UV-VIS and IR Spectroscopy). He/she will also have the opportunity to perform the in vitro tests aimed at evaluating the efficacy of the synthesized derivatives.

Contacts:

ines.mancini@unitn.it

alessandro.quattrone@unitn.it

denise.sighel@unitn.it

Starting date: from October 2019

Three theses available preferentially for master ...
Monday 01 April 2019

Three theses available preferentially for master students in 2016 at the Laboratory of Translational Genomics (http://web.unitn.it/en/cibio/11877/laboratory-translational-genomics; https://quattronelab.wordpress.com/) of the Centre for Integrative Biology of the University of Trento.

 

1.

Exploiting development: epitranscriptomics for novel therapeutic strategies in neuroblastoma

Neuroblastoma is a tumor of the developing nervous system that accounts for over 50% of all pediatric cancers and poses significant challenges to developing more effective and less toxic therapy. Post-transcriptional modification of RNA might be an important mechanism driving the onset of embryonic and prenatal tumors, as its biological function has been proven to be essential during embryogenesis and development.

N6-methyladenosine (m6A) has been recently discovered as the most prevalent internal modification of mRNA. Last pieces of evidence support the notion that balanced regulation of gene expression via m6A is mainly involved in self-renewal and differentiation of stem cells. The primary goal of this project is to understand possible implications of epitranscriptomic modifications in cancer development. Precisely, we believe that altered or merely enhanced m6A methylation in tumors may guide translation of specific target mRNAs that are directly involved in regulating embryonic features. Since neuroblastoma is likely and “embryonal tumor” in which only a few somatic driving mutations that are eligible for targeted therapy have been characterized, alteration of translation during the neurodevelopmental path may represent an efficient source of clinical exploitation.

 

 

2.

Cancer as infection: mitochondrial translation as a therapeutic target in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most advanced form (IV grade) of astrocytoma and the most common primary brain tumor in adults. Currently, the therapies available for its treatment give a very modest improvement of the average 14-month survival after diagnosis.

Recently, some solid tumors in their advanced form have been shown to depend on oxidative phosphorylation as the energy source for their development and the growth advantage. In particular, this seems to be the primary energy constraint for cancer stem cells and metastatic cells, as opposed to the well-known general dependence of bulk cancer cells on aerobic glycolysis (the so-called Warburg effect).

Oxidative phosphorylation is made possible by the protein complexes of the electron transport chain, of which 13 components only are encoded in the mitochondrial genome and translated by the mitochondrial translational apparatus. The production of these 13 proteins seems to be the limiting factor in electron transport complex stoichiometry. Mitochondrial ribosomes and polysomes are highly similar to those of bacteria, and are well know to be a toxic target of those antibacterial antibiotics - 40% of the total in use -, targeting bacterial translation.

We already completed a screening from a focused library of 180 ribosome-targeting antibacterial antibiotics in GBM cells in culture and identified by high content screening analysis some hits (compounds able to suppress mitochondrial translation and later kill cells.

 

 

3.

TDP-43 as the “Guardian of the Transcriptome”: enhancing nonsense-mediated decay to fight Amyotrophic Lateral Sclerosis

Our aim is to validate a new drug target in ALS with TDP-43 proteinopathy, the nonsense-mediated decay (NMD) program. The reason comes from our recent discovery of a role for TDP-43 in NMD enhancement in the cytoplasm, both in vitro and in vivo (still unpublished). Together with the very recently uncovered function of TDP-43 in prevention of incorrect splicing of nonconserved cryptic exons, this feature identifies a coherent, nucleocytoplasmic role of TDP-43: preventing intronic insertion in mature mRNAs and promoting mRNA degradation by NMD when bearing these insertions. In our view, this key «guardian of the trascriptome» role of TDP-43 brings to NMD inhibition when motor neurons develop TDP-43 proteinopathy, which in turn elicits the unfolded protein response (UPR) pathway because several NMD targets are active UPR inducers. UPR progressively kills motor neurons, promoting the ALS phenotype.

With this model in the background, we will look for small molecule antagonists of the NMD-UPR axis. We will screen both upstream of the axis (compounds able to enhance NMD in TDP-43 mutant, UPR active motor neuron cells), at the axis junction (compounds able to suppress IRE1α activity), and downstream (compounds able to suppress UPR). Again in cells, we will also test for synergism of compounds belonging to two different classes.

We will finally validate the best hits in two zebrafish and a mouse mutant TDP-43 models.

 

Interested students are requested to email to prof. Alessandro Quattrone: alessandro.quattrone@unitn.it