Page 47 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

A monoclonal antibody 5E1 (ch5E1) from murine-human chimeric has been proven to bind Shh and thereby to inhibit Hedgehog signaling[85]. A small molecule (Robotnikinin) was also identified as a Hedgehog signaling inhibitor in a microarray-based screening effort. Robotnikinin binds to Shh thereby inhibiting the activation of Hedgehog signaling [86]. Other new ligand processing blocking agents have been identified in high-throughput screens and appear to have different mechanisms of actions, including interfering with Shh palmitoylation by targeting Hh acyltransferase[87, 88]. These molecules have obvious potential as they also target non-canonical Hedgehog signaling.
Gastric cancer Treatment using Hh pathway targeted agents.
For gastric cancer treatment using Hh signaling targeted agents, only two clinical trials have been performed. A phase II multi-centered, randomized, a prospective clinical trial involving 124 participants was performed to determine the vismodegib efficacy, potency, and safety. For adenocarcinoma patients under FOLFOX chemotherapy, vismodegib an SMO inhibitor was administered in conjunction with this regimen. The study did not meet the primary endpoint with a no significantly- improved progression-free survival between the placebo group and vismodegib group (9.3 months vs. 11.5; p = 0.34), although with a noticeable tendency for prolonged progression-free survival[89]. The lack of a statistically significant result may well stem from this study being underpowered. Lack of good biomarkers that can act as surrogates for progression-free survival can also be considered a confounding factor. CD44 immunopositivity has been established as a biomarker of gastric cancer stem cells. CD44 expression was analyzed in phase II clinical trial samples of gastric tumors and were associated with improved survival. Patients who received chemotherapy alone had poor survival together with high CD44 suggesting a potential role for CD44 as a biomarker in the treatment of patients with Hedgehog signaling targeting agents[78]. In addition a BMS-833923 maximum tolerable dose phase 1 clinical trial has been performed. Capecitabine and cisplatin were used in combination with BMS-833923 in drug naïve adenocarcinoma patients. The study was completed in 2013, but the findings have not yet been reported (NCT00909402). Thus a potential role for Hedgehog inhibition in gastric is far from evident and requires more clinical testing.
Gastric cancer and the Hedgehog Signalling
Gastric cancer and Hedgehog signalling
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