Select year:

Activity Report IFOM 2007

More to explore

Complete list of IFOM Publications 2007

In 2007, IFOM scientists published 111 research articles in international scientific journals, with an average impact factor of 9.016

Lung cancer: the signature of metastasis
A new therapeutic target for acute myeloid leukemia: the PRDM16 gene
Topoisomerases and DNA replication

Lung cancer: the signature of metastasis

One of the highlights of the 2007 publications was the research directed by Pier Paolo Di Fiore, published in the November issue of the Journal of Clinical Investigation.

Bianchi F, Nuciforo P, Vecchi M, Bernard L, Tizzoni L, Marchetti A, Buttitta F, Felicioni L, Nicassio F, Di Fiore PP; "Survival prediction of stage I lung adenocarcinomas by expression of 10 genes"; J Clin Invest; Nov;117(11):3436-44; 2007; IF:15.754 PMID 17948124

Through experiments conducted on experimental models and on human tissues obtained from lung cancer patients, scientists identified a group of ten genes that are frequently altered in certain lung tumours and that can distinguish those patients who have a high probability of developing metastases. "It's a very significant result - explained Fabrizio Bianchi, first author of the study - and it holds great clinical promise, because the tumours that we studied are all at 'stage 1', which is an early stage in the development of the disease. Normally, these tumours are small and treatment is purely surgical, but, unfortunately, a percentage of these patients will go on to develop metastases. The group of genes that we identified form what we call a prognostic 'signature' of metastasis, which can help to define the most appropriate therapy for these patients." Patients with tumours that display this signature have a higher risk of developing metastases and could be recommended for adjuvant chemotherapy, a treatment that is not usually administered to patients with stage 1 lung cancer. A clinical trial will shortly begin to assess the usefulness of this finding as a prognostic marker. "We will try to understand - concluded Bianchi - if treatment with adjuvant chemotherapy in patients that present this alteration can reduce the incidence of metastasis."

^ top

A new therapeutic target for acute myeloid leukemia: the PRDM16 gene

Progress in the field of acute myeloid leukemia was published in the December issue of the Journal of Clinical Investigation by Pier Giuseppe Pelicci's group.

Shing DC, Trubia M, Marchesi F, Radaelli E, Belloni E, Tapinassi C, Scanziani E, Mecucci C, Crescenzi B, Lahortiga I, Odero MD, Zardo G, Gruszka A, Minucci S, Di Fiore PP, Pelicci PG; "Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice"; J Clin Invest; Dec 3;117(12):3696-3707; 2007; IF:15.754 PMID 18037989

Scientists in Pier Giuseppe Pelicci's group have been working on experimental models and confirming their results directly in patient-derived leukaemic cells. In this way, they identified and characterised a lesion in the PRDM16 gene, which is "overexpressed" in myeloid leukaemia (every gene "codes" for a protein, i.e. it contains the instructions necessary for a cell to produce a particular protein: in essence, an "overexpressed" gene "works too much", causing the cell to produce excess amounts of its encoded protein). The molecular mechanism that allows the disease to develop, after the start of the neoplastic process, was obscure to date. The new discovery sheds light on this process. "Today, we have a good understanding of the genetic alterations that trigger leukaemia - explained Pelicci - but, until now, we didn't know which alterations sustained the subsequent progression of the disease. We knew the so-called 'initiators', but not the 'successors'. Here, for the first time, we describe a 'successor' that is present in 40% of all myeloid leukaemias." Naturally, the objective of scientists is to obtain a detailed understanding of the molecular phases of disease onset and development, and to identify weak points in the process (i.e. "therapeutic targets"). This will allow the development of targeted therapies, aimed at these weak points; such treatments will be more effective and less invasive than current treatments. "Our result - continued Pelicci - is promising for future therapies, because PRDM16 is an enzyme, and enzymes are relatively easy to inhibit pharmacologically." The way forward, therefore, is to study the PRDM16 gene in further detail, as it potentially represents a good therapeutic target.

^ top

Topoisomerases and DNA replication

Marco Foiani has continued his in-depth study of the molecular mechanisms controlling the cell cycle and genome integrity, and published his findings in the August issue of Genes and Development. This study localised "fragile" regions of the genome, which are more prone to accumulate cancer-causing DNA breaks.

Bermejo R, Doksani Y, Capra T, Katou YM, Tanaka H, Shirahige K, Foiani M; "Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation"; Genes Dev; Aug 1;21(15):1921-36; 2007; IF:15.05 PMID: 17671091

"For this study - explained Foiani, Scientific Co-Director of IFOM - we concentrated on topoisomerases: enzymes that are involved in various aspects of DNA replication. During this process, which preludes cell division, the DNA twists up and essentially becomes knotted. However, for DNA replication to proceed successfully, these 'knots' need to be undone, otherwise genetic alterations occur that can trigger the onset of tumours. Topoisomerases do just this: they undo the knots in DNA. We have chosen to study these enzymes, which are also directly involved in DNA repair, because of their fundamental role in DNA replication." Scientists employed a "genomic approach" to explore the precise regions in the DNA at which topoisomerases were active. "We have discovered - explained Foiani - the exact regions where DNA breaks occur when topoisomerase malfunctions. This is an important step forward, because, although we knew that these 'fragile regions' existed, we did not know where they were located. Now we have 'unmasked' another cellular process that precedes DNA breakage." This is not the end of the story. Since some traditional anti-cancer drugs act on topoisomerases, Foiani's findings provide the molecular mechanism of action of these "old generation" drugs. So, these findings could help in the development of new drugs, based on the same underlying principles, but with greater selectivity and specificity. In the immediate future, Foiani and colleagues will continue to work on the molecular mechanisms of topoisomerases. "We are interested - concluded Foiani - in understanding certain important, and thus far, neglected, aspects of the processes involving these enzymes. For example, why do knots form in DNA? And why do they form in those precise regions, but not in others?"

^ top