In order to improve the prognosis of patients with Malignant Pleural Mesothelioma (MPM) no question additional many efforts shouid be done to understand if some specific metabolic abnormalities of MPM do exist and, if they do, how these can exploited for therapeutic purposes.
Fondazione Buzzi's program encompasses a broad range of research project aimed at bridging the gap between pre clinical and clinical sciences in order to set up innovative treatment for this orphan neoplasm.In particular two projects of this program focused on translation mechanism and oxidative pattern of mesothelioma cells respectively.
Where we are and where we are heading
Translation abnormalities of MPM cells: translational implications
Previous data suggested that adhesion and spreading of mesothelioma cells on ECM require the translation of pre synthesized mRNAs, and mTORC1 activity and spreading of mesothelioma cells is rapamycin sensitive and requires continuing translation. More recently it has been showns that the sensitivity of global translation to mTOR Inhibition in these same cells depends on the equilibrium between eIF4E and 4E BP1 but (rather surprisingly) it is not dependent on external growth factors. Moreover many MPM cells are low sensitive to mTOR pathway ihibition whereas the sensitivity to mTOR inhibition is driven by eIF4E and 4E BP proteins espression. More in details low eIF4E and high 4E BP expression are related to mTOR inhibitors sensitivity respectively. Hence we evaluated these proteins in specimens from patients with MPM to predict their sensitivity to MTOR inhibitors.Serine235 phosphorilation of translation factor eIF6 plays a key role in murine tumorigenesis and can be an attractive therapeutic target. IHC staining in specimes from patienst with MPM revealed eIF6 overepression in a high number of cases.On the light of these results eIF6 inhibition either by lentiviral vectors or by PKC beta Kinase inhibithor Enzastaurin has been assessed on in vitro and in vivo experiments with promising results that could lead to tailored clinical treatment of patients with eIF6 overespression
Oxidative Energy metabolism of MPM cells: Estrogen Receptor (ERb) is a new therapeutic target for MPM an the other ERb overespressing tumours
Female Gender is a well known positive prognostic factor for patients with MPM and ERb overespression has been demonstrated to be associated with better prognosis too. More recently we also demonstrated how ERb interferes with EFGR espression and affects the sensitivity of MPM cells to EGFR inhibitors. Now we clarified a novel mechanism by which ERb exerts a tumour suppressive effect on MPM cells disclosing a novel therapeutic approach to this neoplasm. Both on in vitro and vivo experiments, ERb activation via either overespression or treatment with selective agonists significantly compromises mitochondrial oxidative pathway (affecting mitchondrial sub units activity) ATP production and decreases cell proliferation and MPM growth.Moreover, due to the impaired mitochondrial activity, ERb overespressing MPM cells turn into a much higher dependency on glicolysis and sensitivity to glicolysis inhibitors. Some selective ERb agonists have been progressively designed over the last few years and are now ready for clinical settings. As ERb espression is common to many human tumours (included prostate and breast cancer) the treatment of ERb positive human with selective ERb agonists is a novel intriguing approach for a subset of cancer patients.
Translation patten and oxidative metabolism of MPM cells seem to disclose a new scenario for the treatment of this tumour even with some implications for "less rare" human tumours.In particular, these studies allowed to disclose novel therapeutic biomarkers of sensitivity to screen our patients.
The next due step is now designing Phase I/II clinical trials for patients with MPM selected on the basis detection of biomarkers that could reasonably predict their sensitivity