Molecular Therapeutics and Exploratory Research
Paolo Comoglio, M.D.
Full Professor, UniTo
Oncogenes involved in invasive growth
Growing evidence prompted us to hypothesize that the metastatic process involves members of the gene ‘super-family’ of tyrosine kinase receptors for ‘scatter factor’, homologues to the Met oncogene (Ron, Axl, Mer and Tyro). Recently, other poorly characterized genes of the family have been identified, Ror1 and Ror2, that can possibly interfere with the response to drugs directed against Met (entered in the clinic), generating resistance.
In the past we have shown that the Met oncogene encodes the receptor for the ‘scatter factor’ HGF. A series of studies - performed for two decades in this and other laboratories - revealed the involvement and the importance of this oncogene in human cancers, demonstrating its key role in the control of ‘invasive growth’, a genetic program driving the metastatic process. We contributed to the development of drugs that inactivate the Met tyrosine kinase: either chemical inhibitors or monoclonal antibodies. These drugs inactivate cancer stem cells in preclinical models of glioblastoma, colorectal and gastric carcinomas, and provide promising results in clinical trials.
Conclusions and perspectives:
We are now working on the characterization of tyrosine kinase receptors of the Met oncogene family (Ron, Axl, Mer and Tyro, Ror1-2) at genetic, biochemical and functional levels. In particular, we are studying their possible interference - positive or negative - with the intracellular signaling triggered by Met during execution of the invasive growth program. Emphasis is given to the study of a hyper-metastatic syndrome, the so-called CUP, metastatic cancer from unknown primary origin.