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Page 8 of 16 Rizzieri et al. J Cancer Metastasis Treat 2019;5:26 I http://dx.doi.org/10.20517/2394-4722.2019.05

TARGETING METABOLIC PATHWAYS FOR THE TREATMENT OF MULTIPLE MYELOMA
The alterations in metabolism provide potentially therapeutic targets for the treatment of MM.

Targeting glycolysis for the treatment of MM
Glucose is the most abundant energy producing molecule in the human body and as such is broken down
to produce energy for the body to maintain its regulatory functions. MM exhibits significant alterations in
glucose metabolism. This was demonstrated by the fact that myelomatous bone and soft tissue lesions have
elevated glucose uptake on positron emission tomography (PET) scans. Total lesion glycolysis and metabolic
18
tumor volume, parameters measurable using F-FDG PET CT scan, are highly associated with progression-
free and overall survival and can significantly improve the prognostic value of both the GEP70 and
[43]
International Staging Systems . These data suggest that targeting specific aspects of glucose metabolism
may offer a novel avenue for therapy.

Like many other tumors, MM cells demonstrate enhanced glycolysis and lactate production (e.g., aerobic
glycolysis) instead of proceeding through the TCA cycle. Enhanced glycolytic flux confers tumor cells a
growth advantage and plays an important role in maintaining myeloma cell survival and proliferation and in
inducing chemoresistance. Many genes are involved in the enhanced glycolysis seen in MM. The PI3K/AKT
pathway, a cytoplasmic chemical messaging system, has been linked to increased glucose metabolism and
may be part of the reason why glycolytic intermediates are upregulated in myeloma cells [44-47] . Subsequently,
[45]
it was found that a serine/threonine protein kinase, mTOR, regulated PI3K/AKT signaling . Hypoxia-
inducible factor-1 (HIF-1) is a transcription factor that is upregulated in the bone marrow microenvironment
(where hypoxic conditions are standard), in myeloma cell lines, and CD138+ plasma cells isolated from MM
patients [48,49] . HIF-1 has been shown to play a key role in the accumulation of increased glycolytic metabolites
in MM [42,50,51] . HIF1-a (a subunit of HIF-1) induces transcription of several genes related to the response to
[42]
hypoxia including genes that upregulate glycolytic enzymes and lactate production . HIF1-a expression is
increased in drug resistant myeloma cells, and is associated with increased risk for metastatic disease and
worse prognosis in various cancers [42,50-53] . Drug resistance and disease relapse are thought to be due to the
[42]
minimal residual disease cells that reside in the hypoxic bone marrow microenvironment. Maiso et al.
showed that specific inhibition of LDHA and HIF1-a can restore drug sensitivity to anti-myeloma agents and
inhibit tumor growth suggesting that targeting HIF1-a or LDHA can be used to inhibit myeloma growth
and overcome drug resistance.

Pyruvate kinase M2 (PKM2) is a key factor regulating aerobic glycolysis and promoting tumor cell
[54]
[55]
proliferation and survival . Recently, Gu et al. showed that never in mitosis gene A (NIMA)-related
kinase 2 (NEK2) regulates splicing of PKM and increased the PKM2/PKM1 ratio in myeloma cells to
promote aerobic glycolysis and oncogenic activity.

LDH is a key enzyme that regulates glycolysis and the conversion of pyruvate and NADH to lactate and
[56]
+
NAD respectively . LDHA has been shown to be upregulated in MM cells by the proliferator-activator
receptor-g coactivator-1b acting on the LDHA promoter. This increase has been shown to significantly
potentiate glycolysis metabolism resulting in increased cell proliferation and tumor growth [42,57] .

MM cells exhibit increased activity in glucose transporters and in key glycolytic enzymes such as HK. Most
of the work targeting glucose metabolism in MM has focused on the GLUT family. Up-regulation of GLUT1,
[58]
GLUT4, GLUT8, and GLUT11 has been shown to increase glycolytic metabolites in myeloma cells . Myeloma
cells rely on the insulin-responsive glucose transporter GLUT4 for basal glucose consumption, maintenance
[58]
of Mcl-1 expression, growth, and survival . Ritonavir is an FDA-approved HIV protease inhibitor and has a
selective off-target inhibitory effect on GLUT4. Treatment with ritonavir elicits dose-dependent abrogation of
[58]
both glucose uptake and proliferation on KMS11 and L363 myeloma cells . Interestingly, a subset of myeloma