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Novel therapeutic antibodies for multiple myeloma

Final Report Summary - MMSC (Novel therapeutic antibodies for multiple myeloma)

The ultimate goal of the proposal was the identification of candidate oncogenes, to provide the scientific and clinical community with thoroughly validated targets, ready to be enlisted into therapeutic programs and ultimately translated into drugs capable to impact on patient survival. We focused on multiple myeloma (MM), the second most common hematological cancer and a deadly disease, with a median survival of 6 years, despite often devastating treatments.
We articulated our proposal in three specific aims:

Specific Aim 1. In vitro assessment of general cancer-relevant activities by an shRNA-based screening.
Specific Aim 2. In vitro gain-of-function studies to evaluate the oncogenic potential of the candidate genes derived from Specific Aim 1.
Specific Aim 3. In vivo validation of the oncogenic potential and response to inhibition of the genes emerging from Specific Aim 2 by shRNA-based screen.

Through this effort, we have identified and validated two genes, encoding for proteins that are amenable to be targeted by either monoclonal antibodies or small molecules. These two proteins, based on our in vitro and in vivo data, may represent novel and more effective therapeutic targets toward the treatment of this deadly disease.
The first gene is overexpressed in patient plasma cells when compared to healthy donors. This gene is an attractive candidate, first, because it belongs to the WNT pathway, critically relevant for MM pathogenesis, and second, it is a receptor tyrosine kinase (RTK). RTKs are often overexpressed and/or mutated in a variety of tumors, causing cellular transformation, enhanced survival, and metastasis. Several RTKs, including c-MET, FGFR3, VEGFR1 and IGFR1, are expressed in MM and there is mounting evidence of their pathogenetic relevance in this disease. The ability of therapeutic antibodies and small molecule inhibitors, like Herceptin, Cetuximab, Gleevec, Tarceva and Iressa, to specifically target RTKs makes these proteins ideal targets for cancer therapies. In vitro and in vivo downregulation of this gene with specific shRNA impacted significantly in several cancer-related phenotypes.
The second gene is also a kinase, entrenched in another developmentally regulated pathway, the Hippo pathway. Again, inhibition of this kinase through shRNAs was able to trigger a DNA-damage mediated apoptosis in a vast array of myeloma cells. A stringent evaluation of the downregulation of this gene, in an in vivo setting, further confirmed the relevance of the inactivation of this protein as a novel tool to unravel cancer cell survival.
These findings would pave the way for a more comprehensive effort, to be conducted eventually in collaboration with SMEs, to devise monoclonal antibodies and small molecules aiming to block the activity and the signaling of these proteins in appropriate patient subsets, ultimately benefiting their quality of life and improving their outcome.
Owing also to this reintegration grant, after having spent several years abroad, I have been able to secure additional funding, branching out in several additional scientific directions; have established an extensive network of national, European and international collaborations; obtained a permanent position in the host institution, thus fulfilling the main goals of this reintegration grant.