Page 173 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy
P. 173

 and thus knowledge of the pathways involved would provide novel targets to stimulate immunity. Excitingly from this analysis Rac/Rho signaling emerges as the pathway targeted by microgravity to inhibit immunity in space travel, implying that stimulation of this pathway might be beneficial in gastric cancer. The same pathway I identified as being downstream of Smoothened in Hedgehog signaling in chapter 4. Thus the analysis in chapter 7 provides further rational for exploring the potential of targeting Hedgehog signaling in gastric cancer. A possibility might be the use of specific Smoothened agonists in combination with Patched antagonists, but requires further exploration.
General discussion
The importance of Hedgehog signaling in many forms of cancer in conjunction with its link to gastric developmental processes has prompted a substantial research effort investigating the potential usefulness of targeting Hedgehog signaling in gastric oncogenesis. As a result, in gastrin-mediated compartment expansion and viral or Helicobacter-dependent gastric carcinogenesis, the role of Hedgehog signaling is now relatively well understood. Furthermore, when the malignant disease is established, the evidence indicates that hedgehog signaling may provoke drug resistance. Now that the Hedgehog inhibitor Vismodegib has come available, which has proved useful in other kinds of cancer (especially basal cell carcinoma), it is tempting to propose clinical trials using this compound for patients who have gastric cancer, and accordingly various of such studies have now been initiated.
Strikingly, however, reports of activating mutations in Hedgehog signaling cascades in gastric cancer are scarce, suggesting that such mutations confer little relative advantage to cancer cells bearing such mutations over those that do not have such mutations. Furthermore, on theoretical grounds, one can expect Hedgehog inhibition to interfere with the clinical effect of conventional medication used to treat gastric cancer.
The data I obtained on Hedgehog signaling may be linked to those I obtained on immuno-checkpoint-directed therapy. Pembrolizumab was shown to have anti-tumor activity in patients diagnosed with advanced, PD-L1 expressing, gastric cancer while causing only limited adverse effects. Suggestive data showed an association between the related immune signature expression and efficacy of the immuno-checkpoint- directed therapy, suggesting this may be a suitable prognostic marker for
                                 Summary
Summary
167
171
8

























































































   171   172   173   174   175