CANCERALIA

Development of novel diagnostic and therapeutic approaches to improve patient outcome in lung and pancreatic tumours

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 Obiettivo del progetto (Objective)

'Lung and pancreatic cancers still have a mortality rate over 85% at 5 years of diagnosis, a clear demonstration of the actual treatment failure and the need for improved clinical management. This involves better tools for diagnosis, prognosis, and selection of sensitive and resistant patients to current conventional therapies or improved innovative treatments as well as the development of novel therapeutic strategies.

The major objective of this proposal is to improve management of patients with either lung or pancreatic tumors by studying the clinical applications of still not investigated metabolic and signalling pathways with the following aims: -development of new tools for early diagnosis -identification of novel tumour markers for early diagnosis and prognosis -prediction of response to conventional treatments -identification of the molecular mechanisms of generation of resistance -development of improved treatments based on the identification of novel molecular targets -design of novel anticancer strategies. -achieve a better understanding of how combinatorial treatments using current standard clinical procedures with novel treatments under development may improve patient outcome.

The proposed consortium is composed of four experimental research groups with a profound knowledge on molecular and cellular biology of cancer, and ample experience in the design of targeted and personalized cancer therapies along with translational research, complemented with three clinical groups with an extensive experience in the clinical management of lung and pancreatic cancer patients, guaranteeing a clinical proof-of principle and applicability, integrating basic-clinical European scientific excellence. Furthermore, the consortium has incorporated one company with direct involvement in critical areas that will make feasible to translate to the clinic the results generated in the project.'

Descrizione progetto (Article)

Recent years have seen extensive investigations into signalling pathways involved in cancer cell proliferation and protein synthesis, providing new avenues for the design of targeted therapies.

Accumulating evidence shows that proteins involved in lipid metabolism such as fatty acid synthase (FAS) and acyl-coA carboxylase (ACA) are overexpressed in cancer cells and are central for tumour growth. Another novel putative cancer marker is the enzyme choline kinase alpha, responsible for the synthesis of the major membrane lipid phosphatidyl choline. Choline kinase alpha is in turn regulated by the Rho family of GTPases through a complex membrane lipid biosynthesis pathway.

Small molecule inhibitors of choline kinase alpha have already reached early clinical trials, supporting the notion that this enzyme and the whole pathway could be explored as avenues of therapy. Based on this, the EU-funded CANCERALIA project will investigate the potential of targeting the biochemical pathways involved in lipid metabolism and small G proteins for the treatment of lung and pancreatic cancers.

Analysis of the lipid and gene expression profiles of over 200 lung carcinomas has revealed some interesting results. Analysis of the single nucleotide polymorphisms (SNPs) in genes involved in the membrane lipid metabolism pathway will hopefully identify genes associated with high risk of lung or pancreatic cancer. This information on the genetic variation of the lipid biosynthesis pathway will also prove useful for prognosis and response to therapy.

Additionally, the CANCERALIA consortium is interested in predicting the response to choline kinase alpha inhibitors. To this end, scientists have developed specific in vitro models of resistant and sensitive tumours and have managed to identify ASAH1 as a possible marker predictive of lack of response as well as a possible new therapeutic target. Furthermore, they are in the process of associating the response to choline kinase alpha inhibitors with gene and lipid expression patterns.

New non-invasive imaging tools will facilitate the evaluation of the activity of choline kinase in vivo. Partners are proposing to use labeled choline precursors for screening patients with lung cancer by positron emission tomography (PET).

The lipid and protein profiles of lung and pancreatic cancers have the potential to generate information on key genes and their association with prognosis and response to conventional therapies. Furthermore, the identification of cancer markers predictive of response to treatments will allow medical professionals to foresee any acquired resistance to therapy.