Ornithine Decarboxylase: Novel Prognostic Marker and Target for Multiple Myeloma Therapy

Multiple myeloma (MM) is an age dependent second most common hematopoietic malignancy which remains incurable despite recent advances in therapies. Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant condition that precedes MM. Dysregulation and mutations of myriad of molecules is implicated in pathogenesis of MM. Cyclins (CCND) are almost universally dysregulated in MGUS and MM, while c-MYC overexpression and sometimes RAS mutations are associated with MGUS to MM progression. c-MYC, because of its strong association in this malignant transformation and it being a master regulatory factor is a logical therapeutic target. But, a therapeutic approach to target c-MYC has not been successful. So a strategy to target either upstream or downstream molecules in c-MYC pathway is worth considering. Ornithine decarboxylase (ODC) is one such downstream effector of c-MYC which regulates polyamine synthesis and thus regulates cell proliferation. ODC is also downstream of RAS which makes it common to two of the important oncogenes involved in MM.

To know whether ODC plays a role in MM pathogenesis, we looked into its gene expression profile in the MM patients. In the Mayo cohort of 100 patients we found significant difference in ODC expression as disease progresses from MGUS to MM. We found significant survival difference in MM patients from this cohort which were divided by ODC expression and this survival difference was more pronounced in non-hyperdiploid group (median survival were for ODC < 1 - 66 mo vs for ODC > 1 - 29.5 mo, Figure 1A) which is a known poor prognostic group. When looked at ODC expression among different TC classes in MMRC dataset, we find ODC expression significantly higher in known high risk and poor prognostic groups 4p16 and MAF than other groups. These findings suggest higher ODC expression associated with poor survival. To further strengthen our observation, we analyzed TT3 group of Arkansas cohort and we observe prolonged event free survival (Figure 1B) and overall survival in patients with low ODC expression as compared to patients with high ODC expression (Figure 1C).

After establishing poor prognostic role of ODC, we wanted to test it as a potential therapeutic target. For this purpose, we employed DFMO (Difluromethylornithine) which is the enzymatic irreversible inhibitor of ODC. We tested 15 different MM cell lines for proliferation with DFMO, majority of them respond to DFMO and IC 50 ranged from 28uM to 70 uM. DFMO generally halted cell cylce in G1S and had a cytostatic effect. We further tested efficacy of DFMO in combination with standard anti-myeloma agents lenalidomide, bortezomib, Vorinostat, melphalan and dexamethasone. We found these combinations to be synergistic except with melphalan where the combination was antagonistic.

We therefore suggest that DFMO, which has a good toxicity profile can be advantageous in MM patients who are relatively old and many times cannot tolerate extensive chemotherapy for its toxicity. Moreover since it is synergistic in preclinical model with two main anti-myeloma agents lenalidomide and bortezomib, it may well be combined with both to decrease the amount of drug needed and hence toxicity. We think it will be especially beneficial to those patients who have high ODC levels. So we propose ODC to be a prognostic marker and therapeutic target in MM.