Background
The tumor and its microenvironment are linked by a complex network of molecular signals that sustain cancer cell survival, preserve cancer stemness, promote neoplastic proliferation and foster tumor invasion. In the last few years, the importance of the tumor-microenvironment crosstalk in modulating tumor progression and in determining the response to therapy has been emerging with increasing evidence. Among the key players in this crosstalk are hypoxia and angiogenesis, which beside more classical signals mediated by growth factors and cytokines represent important targets for therapeutic intervention.
Achievements
Paolo Michieli and his group have been focusing their research on the pro-invasive signals mediated by Hepatocyte Growth Factor and of its high affinity receptor, the tyrosine kinase Met, which play a key role in sustaining tumor angiogenesis, invasion and metastasis. Their work has always been oriented to understanding and treating cancer in experimental systems. Their major achievements include the development of several engineered cytokines that protect normal tissues against the deleterious effects of chemotherapy and radiotherapy, and the engineering of a series of growth factor antagonists that can be used as anti-cancer drugs. Using mouse models of cancer, they provided proof-of-concept that blockade of Hepatocyte Growth Factor and of Met inhibits tumor growth, reduces tumor angiogenesis and suppresses metastatic spread. Nowadays Met and Hepatocyte Growth Factor are established targets for cancer therapy and many drugs are being tested in clinical trials. Michieli and colleagues are also pioneers in the field of tumor hypoxia. A few years ago they unveiled a fundamental molecular mechanism linking low oxygenation to metastasis, providing a molecular explanation to the increased aggressiveness of hypoxic lesions. This finding has important biological implications relevant to anti-angiogenic therapy. When we attempt to ‘suffocate’ a tumor by cutting off its blood supplies, we do reduce tumor growth but at the same time we induce cancer cells to escape and disseminate, in search of a more oxygenated environment. This phenomenon is real and now well documented: angiogenesis inhibitors are also potent promoters of metastasis. Michieli and his group are currently developing anti-invasive drugs that can help prevent this adverse side effect of anti-angiogenic therapy.
Goals
The Laboratory of Experimental Therapy and Gene Transfer is currently involved in the generation of monoclonal antibodies that block the activity of Hepatocyte Growth Factor and of Met, and in the development of mouse models that allows the testing of their activity. Michieli and colleagues are also studying potential clinical applications of these biological agents, either as a monotherapy or in combination with other drugs or treatment. A major objective of the Laboratory of Experimental Therapy and Gene Transfer is to develop appropriate therapeutic strategies that allow overcoming hypoxia-mediated metastasis and drug resistance. A second objective is the development of innovative gene therapy tools for the treatment of cancer. Thanks to the joining of Dr. Elisa Vigna’s group (formerly the Laboratory of Gene Transfer and Therapy), the Laboratory of Experimental Therapy and Gene Transfer has now all the necessary know-how to operate also in the field of lentiviral vectors.
Internal collaborations
The Laboratory of Experimental Therapy and Gene Transfer collaborates with the Laboratory of Transgenic Mouse Models for the set up of novel mouse models of cancer, the Laboratory of Pharmacology for the testing of targeted drugs on human biopsy-based mouse xenografts, and with the Laboratory of Cell Adhesion Dynamics for the development of new pharmacological agents directed against human endothelial cells.
