Molecular therapy for multiple myeloma.
OBJECTIVE
Several molecular and cytogenetic advances have suggested novel therapeutic strategies that could help reach an eventual cure for multiple myeloma (MM).


METHODS
Identification of novel, "MM-specific" molecular targets should pave the way for drugs that can specifically attack the neoplastic cells while sparing the normal ones. Drugs that alter the marrow microenvironment--such as bisphosphonates, proteasome inhibitors (e.g. PS-341/LDP341), lactacystin or LLNV compounds--induce apoptosis or G1 growth arrest and alter the adhesion of MM cells to marrow stroma. These drugs that modified microenvironment have a more solid scientific basis and may therefore have more realistic implications in MM treatment. Of these, novel vascular endothelial growth factor (VEGF) inhibitors, such as SU5416 and SU6668, block tumor-cell adhesion and could disrupt MM cell proliferation. Similar tyrosine kinase inhibitors (TKI) such as fibroblast growth factor receptor (FGFR) inhibitors may serve when the FGFR3 gene is overexpressed due to the t(4;14)(p16.3;q32) and/or is activated by point mutations. In cases carrying the translocation and expressing the IgH/WHSC1-MMSET hybrid transcripts, histone deacetylase (HDAC) inhibitors could be useful, but their possible clinical use need to be supported by more biological studies. Tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) induces apoptosis in MM cell lines and primary cells. The proliferative signaling pathway of FGFR3 is mediated by Ras (Ras-activating mutations are frequently found in MM), which presents a possible target for farnesyltransferase inhibitors (used alone or in association with IFN-alpha).


CONCLUSIONS
In several of these options, preclinical studies have proved encouraging, and clinical trials are now getting underway.
Martinelli
G
G
Molecular Biology Unit, Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, via Massarenti 9, 40138 Bologna, Italy. gmartino@kaiser.alma.unibo.it
Tosi
P
P
Ottaviani
E
E
Soverini
S
S
Tura
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*
D000970:Antineoplastic Agents; D001685:Biological Factors; D004791:Enzyme Inhibitors