Metabolic starvation triggered by l-asparaginase sensitizes multiple myeloma cells to proteasome inhibitors by inducing DNA damage accumulation
Creators: name: MINETTO, PAOLA
Publisher: name: Universit� degli studi di Genova
Year: 2019

description: Multiple Myeloma (MM) is a malignant proliferation of clonal bone marrow (BM)
plasma cells (PCs) in association with monoclonal protein. Despite the dramatic
improvements in MM treatment achieved in the last decade, it is still an incurable
disease. A better knowledge of the biological mechanisms involved in disease
occurrence and progression has led to the development of several new, innovative,
drugs that significantly improved patients outcome and renewed the therapeutic
approach to the disease in the last years. However, resistance develops with a 40%
survival at five-years. Moreover, despite the improvement of patient riskstratification
systems at diagnosis, treatment outcome is often unpredictable due to the high degree of genomic heterogeneity and genomic instability which characterize the disease. In this view, novel therapeutic strategies capable to overcome disease heterogeneity and improve patient outcome are strongly needed.
A fundamental feature of all cancers is the metabolic reprogramming to promote
growth, survival, proliferation, and long-term maintenance. The common feature of
this altered metabolism is increased glucose uptake and fermentation of glucose to
lactate, the so called ?Warburg Effect?. Moreover, the non essential amino acid
Glutamine complements glucose to meet cancer cells metabolic demands. In
particular, some human tumors exhibit a high requirement for Gln for anabolic and
metabolic processes, a condition that has been defined ?Gln-addiction? leading to the
investigation of such Gln-dependence as therapeutic target in human cancers. Beside its role of carbon and nitrogen source for macromolecules synthesis, the
metabolism of this non-essential amino acid support tumor growth by inducing
essential amino acids uptake and activation of mTORC1 signaling pathways, which acts
as regulator for protein translation and autophagy. Moreover, Gln maintains
mitochondrial membrane potential and prevents oxidative damage driving Glutathione
(GSH) and NADPH synthesis.
In the recent years the importance of Gln metabolism as therapeutic target began to
be explored and emerging data suggest that inhibition of glutamine metabolism with
small molecules results in an energetic crisis leading to cellular death. Emerging
data suggest efficacy of Gln-deprivation also in MM cells which are unable to
synthesize adequate amounts of Gln and, therefore, result highly sensitive to Glntransporters blockade or glutaminase inhibition.
Several approaches are reported to achieve Glu-depletion including: uptake inhibition
(Gln-transporters inhibitors), metabolism targeting (Glutaminase inhibitors) or serum
depletion exploiting the glutaminase-activity of L-asparaginase drug (L-ASP). L-ASP is a
bacterial-derived enzyme that induces serum aminoacidic deprivation by catalyzing the
hydrolysis of asparagine in aspartic acid and ammonium and glutamine in glutamic acid
and ammonium. Among the above mentioned strategies to obtain Gln-deprivation,
L-ASP is already available in clinic as it represents a cornerstone for acute
lymphoblastic leukemia (ALL) and some aggressive lymphomas treatment.
Based on these observations, we aim to explore the therapeutic relevance of
Asparaginase-induced Gln depletion alone and in combination with currently usedanti-MM drugs. Moreover we will analyze biological mechanisms supporting the
effectiveness of the identified therapeutic strategies.