56
The mTOR belongs to the PI3K-related kinase family and is
frequently activated in gastric cancer. It is responsible for regulat-
ing critical physiological functions of cell growth, cell proliferation,
and cell cycle via the PI3K/Akt/mTOR signaling pathway [ 28 ].
Everolimus is an oral mTOR inhibitor and has been approved for
metastatic renal cell carcinoma [ 29 ] and breast carcinoma [ 30 ].
Stomatitis is common and pneumonitis is infrequent but severe
adverse effects of everolimus. Everolimus initially demonstrated
significant clinical benefit in a phase II study (testing of drug on
patients to assess efficacy and side effects). In the 53 patients with
advanced gastric carcinoma who have progressed after one to two
lines of chemotherapy, everolimus achieved disease control in over
half of the patients and the median progression-free survival and
overall survival were 2.7 months and 10.1 months, respectively
[ 31 ]. The GRANITE-1 study was a phase III multicenter study
that randomized patients, including around 30% of patients with
esophagogastric junction adenocarcinoma, to receive everolimus
or placebo after one or two lines of chemotherapy [ 32 ]. The study
failed to show improvement in overall survival and progression-
free survival. The fact that patients enrolment was not stratified
and that high proportion of patients have received post-progres-
sion treatment may explain the negative result of the study. A bio-
marker analysis from the GRANITE-1 study is ongoing and
hopefully would identify predictive makers in the PI3K/Akt/
mTOR pathway.Olaparib is a first-in-class oral poly ADP-ribose polymerase (PARP)
inhibitor that exploits tumor DNA damage response pathway defi-
ciencies to preferentially kill cancer cells and has been approved by
the Food and Drug Administration (FDA) of the USA in BRCA-
mutated advanced ovarian cancer in 2014 [ 33 ]. In gastric cancer,
olaparib was first shown to improve overall survival significantly
when combined with paclitaxel in the second-line setting in a phase
II Asian study. Patients with low expression of ataxia telangiectasia-
mutated (ATM) protein appeared to have more benefit. However,
a subsequent phase III randomized study of paclitaxel with or
without olaparib did not reproduce the positive results of the phase
II study. Olaparib plus paclitaxel did not increase the overall sur-
vival, progression-free survival or response rate in the whole study
population or in the low ATM subset although the combination
was well tolerated [ 35 ].Claudin 18 belongs to the claudin family of proteins, which are
responsible for forming tight junction in epithelial cells, and clau-
din 18.2 is an isoform abundant in gastric adenocarcinoma [ 36 ].
IMAB362 is a chimeric monoclonal anti-claudin 18.2 antibody
that activates complement and antibody-dependent cellular cyto-
toxicity. IMAB362 plus EOX (epirubicin, oxaliplatin, and1.3 Mammalian
Target of Rapamycin
(mTOR)
1.4 Poly ADP-Ribose
Polymerase (PARP)
1.5 Claudin 18.2
Ka-On Lam and Dora L. W. Kwong