CURELUNG

Determining (epi)genetic therapeutic signatures for improving lung cancer prognosis

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 Obiettivo del progetto (Objective)

'Lung cancer (LC) is still the most lethal type of cancer worldwide. The extremely poor prognosis for LC patients is partly due to the lack of effective therapies. At present, most patients with pulmonary carcinomas are treated with chemotherapy. This essentially consists of classic cytotoxic drugs which only improve survival in small cohorts in few cases. In spite of the rapidly growing understanding of the epigenetic and genetic profile of LC, such knowledge has contributed little to improving therapeutics. This scenario, however, is likely to change soon because several specific cancer therapies, targeting molecules that are altered in cancer, are being developed or are already undergoing clinical trials. Thinking ahead, our proposal focuses, on the one hand, on validating novel and specific therapeutic strategies, with particular emphasis on discovering (epi)genetic alterations that could act as novel targets for therapies, and, on the other, on defining the (epi)genetic markers that could determine the efficacy response or resistance to targeted therapies as well as the acquired resistance of the tumours to therapy. To reach our goals, we have designed an integrative and interdisciplinary approach involving leading European clinical scientists of international renown with prominent preclinical and basic research groups using high throughput and state-of-the art platforms for genomics and gene expression analysis. To date, no such comprehensive information exists. The results will be of great value for the stratification of lung tumours according to their genetic background for tailored treatments. The development of an (epi)genetic-based therapeutic prediction model will hopefully set the basis for future tailored treatment of LC as well as of other epithelial cancers.'

Introduzione (Teaser)

The advances in genome analysis technologies have geared cancer research towards novel paths of biomarker and therapeutic target discovery. A thorough omics analysis by the Curelung consortium aims to characterise the genetic profile of lung cancer and identify novel targets for therapy.

Descrizione progetto (Article)

Understanding cancer genomes has led to the design of targeted therapies against proteins altered in cancer cells, such as tyrosine kinase growth factor receptors. In the case of lung adenocarcinomas, mutated epidermal growth factor receptor (EGFR) proteins or translocations of ALK constitute targets that are currently being exploited therapeutically.

The EU-funded project 'Determining (epi)genetic therapeutic signatures for improving lung cancer prognosis' (Curelung) has emerged as the joint effort of leading European groups in the field of lung cancer to help define the genetic and epigenetic profile of this cancer type. By using state-of-the-art techniques, the consortium aims to identify novel targets and markers that will serve to personalise cancer treatment.

In the initial steps of the project, a genetic profile of alteration known cancer genes in lung cancer cells served to establish the profile, to define the frequency and to determine the accumulation in specific histopathological subtypes of each gene alteration. Further, the global gene expression and single nucleotide polymorphism (SNP) analysis unveiled the presence of inactivation at a novel tumor suppressor gene, PARD3, involved in cell polarity.

This molecular and genetic analysis was combined with histological evaluation of lung cancer samples from patient cohorts from different groups within the consortia. The overall frequency of PARD3 inactivating alterations was about ten percent of the tumors, most of them accumulating in the squamous cell carcinoma (SCC) subtype.

Furthermore, next-generation sequencing in lung primary tumors of the small cell lung cancer (SCLC), has served to identify recurrent mutations in histone-modifying genes (CREBBP, EP300 and MLL), among others involved in axon guidance and cellular migration.

These novel alterations found in lung SCC and SCLC are of great interest, since the genetics of these types of lung tumors are scarcely known.

On the other hand, methylation analysis points towards an overall hypermethylation or differential methylation pattern in lung cancer cells, indicating that gene silencing is a frequent event. The microRNA (miRNA) expression and splicing profiles have granted scientists with other means of predictive power that could be used to differentiate tumor from normal tissue.

Ongoing work towards the development of lung cancer models will aid the efficacy screening of various drugs. A library of 267 small organic molecules of diverse chemical classes is being tested for its potential to target several oncogenic signalling pathways and molecular targets.

Curelung partners are hopeful that the characterisation of (epi)genetic alterations in lung cancer will lead to improved diagnosis and novel therapeutic approaches.