• Mission
• Maps and Directions
• Contact Us
• Directory
• Combining Basic Research and Clinical Trials
• Links

• Administration
• Atherosclerosis and Thrombosis
• Bionutrition
• Biostatistics and Informatics
• Core Laboratory
• Diabetes and Metabolism
• Emergency Care
• Genomics
• Hemostasis and Thrombosis
• Neurology
• Nursing
• Oncology
• Pharmacogenomics

PHARMACOGENOMIC UNIT

Director: Fiamma Buttitta
Phone: +39 0871 357408; 0871 541343
E-Mail: fbuttitta@unich.it

Pharmacogenomics is the study of how genetic inheritance influences the response to drugs, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable loss of efficacy are the main causes of chemotherapy failure in improving patient survival. Human cancers are highly heterogeneous diseases. Regulatory pathways need to be perturbed to transform a normal human epithelial cell into a malignant cell. Any pathway can be altered by changes at any step by a wide variety of mechanisms. These include somatic DNA alterations in tumor cells including mutations, translocations, deletions, and amplifications as well as epigenetic changes which influence gene expression. This combination of genetic and epigenetic mechanisms in these key pathways indicates that cancer can emerge from a complex mix of events, and that no two tumors are likely to have exactly the same underlying genetic changes. This is the reason why the conventional pharmacological approach may have severe limitations. Over the last few years, the focus in oncology drug development has switched from the development of broad acting cytotoxics to that of new therapies directed against specific molecular targets (targeted therapy). Inhibition of tyrosine kinase receptors, associated with signaling, by selective small molecule inhibitors, is emerging as a new strategy for treatment of hematologic malignancies and solid tumors, including non-small cell lung cancer, and gastrointestinal stromal cell tumors. In lung cancer, the identification of somatic mutations in the tyrosine kinase domain of the EGFR gene represents the most important molecular marker of sensitivity to EGFR tyrosine kinase inhibitors and patients carrying these somatic mutations are more likely to respond to EGFR inhibitors. The identification of such mutations has significantly changed the treatment of metastatic NSCLC patients.

This Pharmacogenomics Unit is focused on the mutational status of the tyrosine kinase receptors implicated in lung, breast and ovarian cancer development and in tumor response to therapy. In particular, our studies conducted in a large series of patients with lung cancer have demonstrated that mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. Patients carrying these somatic tumor mutations have a dramatic response when treated with novel targeted therapies, as gefitinib or erlotinib. In addition, in a large series of lung cancers we evaluated the mutational status of other genes involved in response to therapy, including tyrosine kinase receptors (HER2 gene, NTRKs), serine/threonine kinases (BRAF) and KRAS. In breast cancer we assessed the prevalence and nature of PI3K mutations, demonstrating that PI3K is the more frequently mutated gene in this neoplastic form and that it is predominantly altered in a particular histotype, the lobular carcinoma. Moreover, we demonstrated a functional difference between mutations in the helical and tyrosine kinase domain. Patients with helical mutation are candidate to early recurrence and death respect to patients without mutations.

We are currently testing, in different forms of cancers, the mutational status of a series of tyrosine kinase receptors, potentially related to chemosensitivity or chemoresistence.