Ugo Pastorino - Ricerca - Progetti di ricerca

Sinossi

Background
Detection of lung cancer at an early stage offers the real potential to reduce mortality with new chances of cure. Blood based biomarkers could improve significantly screening performance of low dose computed tomography (LDCT). We recently reported the results of a large validation study indicating that plasma microRNAs (miRNAs) have predictive, diagnostic and prognostic value and that combination with LDCT is associated with fivefold reduction on false positive rate for lung cancer. However, for further refinement of miRNAs as biomarker, testing its performance during post-surgical follow-up and across histological and molecular heterogeneity of lung tumors is worthwhile. In addition, preclinical models recapitulating tumors heterogeneity, such as patient-derived tumor xenografts (PDXs, also called avatars) engrafted into immune-compromised mice, might predict better than standard cell-line models and the clinical activity of novel therapeutic approaches, such as miRNA therapeutics, in screen detected lung cancer patients.

Hypothesis
Linking tumor genomics to circulating miRNA profiles represent an attractive approach. It is conceivable that tumors shape their own microenvironment according to individual molecular profile, by affecting the neighbouring inflammatory and stromal components, and that such cross-talk can produce a differential miRNA release into the bloodstream. Therefore, testing the performance of plasma miRNA as a ‘liquid biopsy’ across molecular subclasses of lung tumors would refine its diagnostic, prognostic and potentially therapeutic value. In addition, the assessment of plasma miRNAs modulation during post-surgical follow-up of patients, would help to establish their value as a monitoring tool. A corollary concept is that establishing preclinical individual models of lung tumors might constitute a functional assay to test their biological and molecular heterogeneity, to be than exploited for individual therapeutic approaches.

Aims
Aims of the present project are: i) Genetic profile of LDCT-detected tumors and correlation with plasma miRNA risk profiles ii) Establishment of PDXs individual models (avatars) from screening-detected patients iii) Preclinical trials of mirRNA replacement/inhibition using PDXs for personalized targeted therapies iv) plasma miRNA assay refinement and analysis of follow-up plasma samples after surgery in patients of screening trials and in clinical series.

Experimental Design
A targeted mutation sequencing approach will be use to characterize genetic profiles of representative series of lung tumors identified in two independent LDCT screening trials. Individual gene mutations or mutation spectrum clusters will be correlated with miRNAs profiles and with risk categorization using a miRNA signature Classifier (MSC) previously generated. A selected series of symptomatic or clinically detected tumors at different stage, will be included to compare tumors genetic complexity and performance of the plasma assay in different clinical settings. Establishment of PDXs individual models and preclinical trials of miRNA therapeutics will be attempted for surgically resected lung tumors within the bioMILD trial. Modulation of plasma miRNAs profiles as tool for disease monitoring will be attempted in resected patients.

Expected Results
This study will clarify the relevance of plasma miRNAs as diagnostic, prognostic and monitoring tools across different clinical and molecular subclasses of lung tumors. Results will also be exploited for the development of novel miRNA based therapeutic strategies.