Page 48 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Clinical Applications
Gastric cancer has long been seen as one of the most difficult gastrointestinal malignancies to treat. Encouragingly, recent progress with targeted therapies offers hope for patients with advanced gastric cancer and is substantially expanding the therapeutic armamentarium with regard to this infaust disease. As these treatments continue to be developed, we must focus on determination of predictive markers, and preferably co-develop drugs with these markers. The mechanisms underlying primary or acquired resistance to targeted agents also should be clarified to help further drug development[12]. Developing anti-Shh monoclonal antibodies as Shh antagonists is an area to explore where Hedgehog signaling pathway can be blocked at different levels[90]. Gastric cancer is a multigenic disorder influenced by Helicobacter pylori infection and salt intaker. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding Hedgehog signaling molecules would be utilized for genetic screening of gastric cancer. Also, cDNA-PCR, microarray, and ELISA detecting aberrant Hedgehog signaling activation would be used for optional therapeutic choice. Genetic testing and precise selection of therapeutic options would contribute to the realization of personalized medicine. Several limitations account for poor treatment outcomes in gastric cancer patients amongst which include tumor heterogeneity. Due to traditional classification of gastric cancer into two categories in casu undifferentiated and differentiated types, obvious biological differences must exist. Additionally, molecular subgroups exist gastric cancer category; these include chromosomal instability tumors, stable genomically tumors, unstable microsatellite tumor and Epstein–Barr virus tumor-positive[91]. It is well possible that stratification for subtype is way forward with regard to Hedgehog inhibition for the treatment of gastric cancer.
Conclusion and future directions.
While there is good evidence that Smoothened inhibition may be useful for a selection of gastric cancers, we feel that its untargeted application on gastric cancer patients, in general, is likely to prove disappointing. In this sense efforts to select patients characterized by unusually high SMO expression in gastric tumor material with high probability to have cancers that are truly dependent on a functional Hedgehog pathway may likely yield positive results. As both approaches are
Chapter 2
Chapter 2
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