Page 66 - Read Online

Page 358 Raczka et al. Cancer Drug Resist 2019;2:356-64 I http://dx.doi.org/10.20517/cdr.2018.004

bevacizumab plus INFα is one of the available first-line treatments in patients presenting with metastatic
disease [20,21] . Published in April 2018, the Phase III CheckMate 214 study of nivolumab plus ipilimumab vs.
sunitinib led to the FDA approval of the combination therapy for treatment-naive intermediate- and poor-risk
patients with advanced RCC. In this study, the combination produced a more favorable overall survival (OS)
and a higher objective response rate (ORR) in the above-mentioned patient groups, but not in the low-risk
group. Likewise, it improved progression-free survival (PFS) in comparison to sunitinib, however these results
did not meet the prespecified statistical significance (P = 0.009) [22,23] .

One of the treatments awaiting approval by The National Institute for Health and Care Excellence (NICE)
is atezolizumab plus bevacizumab, which was shown to improve PFS as a first-line treatment of advanced
[24]
or metastatic RCC in comparison to sunitinib . A Phase Ib/II study of lenvatinib plus pembrolizumab
involved 30 patients with metastatic RCC, of which 21 (70%) developed grade 3 or 4 adverse events (AEs) and
[24]
four discontinued treatment due to the AEs . This study reported manageable AEs and did not identify
[25]
any new safety concerns. A Phase III study of this combination vs. sunitinib is underway . Combinations
of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab were tested in a Phase I study
and its expansion trial. Both combinations were evaluated for favorable efficacy and tolerability in patients
with mRCC and other genitourinary malignancies [26,27] . Safety and toxicity of tivozanib plus nivolumab were
[28]
ruled to be acceptable in a Phase Ib study . Of 18 patients, all developed at least one AE and five (38%)
showed signs of grade 3-4 AE. Additional patients are currently being enrolled and treated in a Phase II trial
[28]
that aims to evaluate combination efficacy .

NOVEL APPROACHES FOR THE TREATMENT OF RCC
Glutamine addiction
Over the past few years, cancer cell metabolism has gained significant interest in the research community
[29]
and metabolic reprogramming is now recognized as one of the hallmarks of cancer . In order to sustain
their rapid growth, malignant cells switch to alternative metabolic pathways, which allow them to increase
energy and nutrient production. Cancer cells are largely dependent on aerobic glycolysis, also known as
“the Warburg effect”, whereas normal cells generate energy by oxidative phosphorylation in mitochondria.
Malignant cells may also rely on a non-essential amino acid, glutamine, which can be as equally important
[30]
as glucose for the survival of tumor cells . In the kidney, glutamine is converted into glutamate by the
mitochondrial enzyme glutaminase (GLS1). Glutamate can then enter Krebs cycle and act as an intermediate
[31]
for biosynthesis of various molecules, such as nucleotides, amino acids and glutathione . Due to its
involvement in the pathways mentioned above, glutamine plays an important role in cell proliferation and
[30]
protection against oxidative stress . Moreover, depleted glutamine levels are often found in the tumor
environment caused by its uptake into cancer cells. This in turn affects T-cell growth, proliferation and
cytokine production, all of which require high energy input. Glutamine metabolism is thought to be of
[31]
particular importance in T-cell activation .

The first small molecule GLS inhibitors, such as 6-diazo-5-oxo-l-norleucine (DON), were first described
in the 1950s and suggested to be useful in chemotherapy. Such early compounds also included azaserine
and acivicin [32,33] . All three drugs are glutamine analogues and bind irreversibly to the active site of the
enzyme, thus inhibiting glutamine binding. Despite promising in vitro data, clinical studies with these
compounds have been restricted due to limited therapeutic activity and severe toxicities [33,34] . Dose-limiting
adverse events are likely due to low selectivity and inhibition of other glutamine-utilizing enzymes, such as
amidotransferases and glutamine synthetase. However, DON has recently been used in clinical studies in
patients with advanced refractory solid tumors, where its combination with PEGylated glutaminase showed
[35]
therapeutic activity and a tolerable toxicity profile .

Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) is an example of the class of allosteric
inhibitors of GLS1. It binds to both free enzyme and enzyme-substrate complexes and forms a stable but