OVERVIEW OF NEW THERAPIES AND FUTURE DIRECTIONS
K Anderson. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
We are now poised to use genomics and proteomics to characterize progression from normal to MGUS to MM, to identify novel treatment targets, to classify MM, to identify targets in individual patients, and to design clinical protocols of targeted therapies.
First, gene profiling demonstrates modulations of transcripts associated with MGUS and MM versus normal individuals, as well as correlating with progression from MGUS to MM.
Second, array CGH identifies unique amplifications (i.e., chromosome 1q21) and deletions in the MM genome and then validated novel genetic targets.
Third, genetic profiling provides the basis for a novel molecular classification of MM,
Fourth, genomics and proteomic studies can identify unique targets for combination therapies of individual patients.
Fifth, genomics and proteomics can provide the framework for designing clinical protocols to enhance cytotoxicity and avoid the emergence of drug resistance.
The agents to be combined include:
1. drugs targeting the MM cell and its BM microenvironment (proteasome inhibitors and immunomodulatory drugs, histone deacetylase inhibitors, and VEGF inhibitors;
2. drugs targeting MM cells at the cell surface (IGF-1R tyrosine kinase inhibitor and CD40 antibody) cytoplasm (hsp 90 inhibitors), mitochondria, and nucleus (telomerase inhibitor); and
3. drugs targeting the BM microenvironment (p38MAPK and IKK inhibitors).
For example, gene profiling has shown that bortezomib induces hsp 90, and that combined therapy with bortezomib and hsp 90 inhibitor 17AAG markedly augments cytotoxicity. Gene profiling showed that hsp 27 transcripts to be induced when MM patients become resistant to bortezomib; this observation, coupled with the known role for upstream p38MAPK regulating hsp 27, provided the framework for using inhibitors of p38MAPK to abrogate hsp 27 expression and thereby restore sensitivity of MM cells to bortezomib in vitro.
Proteomic studies show that bortezomib inhibits DNA repair, providing the preclinical rationale for trials combining bortezomib with Doxil or melphalan. Our cell signaling data shows that thalidomide and revlimid trigger caspase 8, and dexamethasone triggers caspase 9 mediated apoptosis, providing the basis for combining these agents to activate dual apoptotic signaling. Bortezomib (caspase 9 and 8) has similarly been coupled with revlimid (caspase 8).
Early studies are rationally combining three novel agents. For example, we have combined proteasome inhibitor Bortezomib with hsp 90 inhibitor 17AAG, since hsp 90 is required for the unfolding of misfolded proteins and their subsequent binding to the 20S proteasome core and degradation. The histone deacetylase 6 inhibitor tubacin binds polyubiquinated misfolded proteins and facilitates their transport to aggresomes, another mechanism for their degradation.
Our preliminary in vitro studies therefore have combined bortezomib, hsp 90 inhibitor 17AAG, and tubacin together to target and inhibit breakdown of misfolded proteins at multiple levels, thereby markedly enhancing MM cell cytotoxicity in vitro. Since it is not possible to evaluate active agents in all combinations, these studies are central and required if we are to translate science to the bedside and rapidly identify the most clinically active combined regimens.
cancereducation.com abstracts/mmrf/62/aays1.pdf |
