*6.2.10. Guanylyl cyclase C inhibitors*

Everolimus is an oral mTOR inhibitor demonstrated to have efficiency in both phase I and phase II studies, which have shown that everolimus monotherapy had a good response rate for advanced gastric cancer patients in the second-line setting [145, 146]. Unfortunately, the phase III GRANITE-1 trial investigating the everolimus monotherapy as a second-/third-line in patients with advanced gastric cancer did not show OS benefit, only the association of severe adverse reactions [147]. Therefore, the use of this agent in the treatment of gastric can-

Rapamycin has shown efficiency in preclinical studies and animal models against gastric cancer, increasing also the effectiveness of chemotherapeutic drugs [148]; nevertheless, its use in

These agents were demonstrated to prevent the cancer cell's single stranded break repair

A phase II trial in metastatic/recurrent gastroesophageal cancer studied the effectiveness of administrating the PARP inhibitor olaparib as a second-line treatment [150], demonstrating improved OS. There is also an ongoing phase III study of second-line treatment using pacli-

Veliparib was developed to increase the effectiveness of DNA-damaging therapies, such as chemo- or radiotherapy. A study of the efficacy of veliparib associated with the FOLFIRI regi-

Because it was revealed that tumors evade host immune recognition [153], immunotherapy has emerged as a novel field of antitumor treatment, which acts by using the blockage mechanism of the inhibitory immune regulatory pathways. New agents targeting immune checkpoints, programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have

Ipilimumab blocks the inhibitory receptor called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Unfortunately, a phase II trial assessing the efficacy of ipilimumab after first-line chemotherapy in unresectable locally advanced or metastatic gastric cancer patients revealed

Nivolumab blocks the interactions between PD-1 and PD-L1 stimulated immune function in vitro, showing antitumor activity in preclinical models. A phase I/II study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with advanced or metastatic solid tumors, including gastric cancer, is still ongoing [155]. Interim results revealed that nivolumab monotherapy demonstrated encouraging antitumor activity in heavily pretreated gastric cancer patients [156]. Furthermore, a phase III trial is currently assessing the tolerability and efficacy of nivolumab in patients with unresectable advanced or recurrent

taxel with or without olaparib in advanced gastric cancer patients [151].

cer needs further investigations.

*6.2.8. PARP inhibitors*

122 Gastric Cancer

gastric cancer does not have enough support yet.

mechanism, leading to tumor cell death [149].

men in gastric cancer is pending results [152].

*6.2.9. Immunotherapy/immuno-checkpoint blockade*

no statistically significant improvement in OS [154].

gastric cancer refractory to standard chemotherapy [157].

been recently investigated.

Guanylyl cyclase C (GCC) is a transmembrane cell surface receptor, expressed both on normal intestinal tissue and on the tumor cells of gastrointestinal neoplasias. MLN0264 consists of a human monoclonal antibody targeting GCC, demonstrating good tolerability of the drug and promising results in a phase I trial in patients with gastrointestinal malignancies expressing GCC [169, 170]. Phase I-II studies of MLN 0264 in previously treated patients with metastatic/ recurrent gastric GCC (+) cancers are currently recruiting patients [171, 172].
