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Page 360 Raczka et al. Cancer Drug Resist 2019;2:356-64 I http://dx.doi.org/10.20517/cdr.2018.004
[42]
models of TNBC . In a patient-derived xenograft model, administration of 200mg/kg of CB-839 twice a
day resulted in 61% tumor growth suppression when compared to untreated control. The HER2 + basal-like
cell line JIMT-1 was used in a cell-line based xenograft model. Two treatment regimens were evaluated: CB-
839 on its own or in combination with the TNBC standard therapy paclitaxel. Administration of paclitaxel
alone led to tumor reduction followed by tumor expansion, whereas CB-839 alone or in combination with
[42]
paclitaxel reduced tumor growth with no tumor regrowth over time .
The activity of CB-839 was tested in a range of kidney cancer cell lines. Exposure to 1 µmol/L CB-839 for
72h resulted in varying degrees of death of most but not all ccRCC lines tested, including 786-O, 769-P and
A498. This variation was not associated with VHL mutant or wild-type status. In contrast, CB-839 did not
[44]
seem to affect growth of six non-RCC cell lines, such as G402 and JMU-RTK2 . Other studies propose that
glutamine becomes the preferred substrate for lipogenesis in VHL mutant ccRCC lines , suggesting that
[45]
glutaminase inhibition should be cytotoxic in these cells.

CB-839 monotherapy
CB-839 safety and tolerability in solid tumors is currently being evaluated in a first-in-man study estimated
[46]
to be completed in September 2019 (ClinicalTrials.gov Identifier: NCT02071862) . The study design contains
both monotherapy and combination arms. As part of the combination, patients will receive CB-839 with
drugs currently used for treatment of RCC, TNBC, NSCLC, mesothelioma and tumors with mutations in
enzymes of the Krebs cycle. This multicenter, open-label, dose escalation study includes patients presenting
with metastatic or locally advanced tumors. As monotherapy, patients will receive 100-800 mg CB-839
twice- or three times daily in cycles lasting for 21 days. The 600 mg twice-daily was selected as the dose
administered to the expansion cohort. In 2016, Calithera reported that 4 out of 75 patients experienced grade
3 or 4 AEs. Out of 19 patients with several previous therapies (median = 3 therapies), 10 were ccRCC patients
of which one achieved a confirmed ongoing partial response as of 8.3 months of therapy. To date, the study
showed that continuous administration of CB-839 is characterized by an acceptable safety profile. Moreover,
it significantly inhibits glutaminase and shows promising signs of clinical activity in various tumors,
including RCC [47,48] .

CB-839 plus everolimus
Everolimus is an inhibitor that targets the kinase mTOR, which is a part of the PI3K/AKT/mTOR pathway
[Figure 1], which is frequently mutated in RCC. Its crosstalk with VHL/HIF creates a positive feedback loop,
where HIF-induced expression of growth factors activates PI3K/AKT pathway through RTKs. This in turn
[49]
activates mTORC1 and mTORC2 leading to upregulation of HIF . HIF translation and the consequent
[50]
angiogenesis can be inhibited by repression of mTOR .
In vitro studies were performed using the ACHN cell line, which is thought to represent papillary RCC given
its chromosomal aberration profile, characteristic c-met polymorphism and WT VHL status [51,52] . Five drug
concentration combinations were evaluated: CB-839 at 18.8-300 nmol/L with everolimus at 1.6-100 nmol/L.
For all combinations, cell survival was lower when compared to monotherapy. Pre-clinical studies of Caki-1
xenografts showed that monotherapy with CB-839 or everolimus, resulted in tumor growth inhibition (TGI)
of 51% and 52%, respectively. However, the combination of the two gave TGI of 85% .
[48]
An ongoing clinical study (ClinicalTrials.gov Identifier: NCT02071862) builds on these pre-clinical data,
[46]
where the two drugs synergize and inhibit glutamine and glucose metabolism when combined . So far it
has shown that the combination is well tolerated in ccRCC and papillary carcinoma patients and CB-839
does not increase the toxicities, compared to everolimus alone. The most common AEs were nausea and
fatigue. A single case of dose-limiting toxicity was attributed to everolimus and after lowering the dose, the
[48]
patient remained on study . A 100% disease control rate (DCR) was reported for ccRCC patients (12/12)
and 67% for papillary RCC patients (2/3). Preliminary PFS for both RCC histotypes was 8.5 months [48,53] .