New Targeted Approaches in Gastrointestinal Malignancies
Ubiquitin, UBL modifiers and the proteasome are key elements that control many vital processes involved in tumor progression. Bortezomib was the first proteasome inhibitor with proven clinical activity; however, proteasome inhibitors have appeared to have a limited efficacy in nonhematological tumors, despite a strong rationale for their use in solid tumors. The clinical activity of bortezomib in patients with advanced gastrointestinal malignancies is disappointing. A deeper knowledge of the molecular mechanisms that govern the UPS is needed to understand why tumor cells are able to bypass the inhibition of the proteasome. Furthermore, there is a clear demand for novel biomarkers that can help to predict the clinical outcome of patients treated with proteasome inhibitors. The combination of proteasome inhibitors with other anti-tumor strategies, mainly tyrosine kinase inhibitors, may serve to overcome resistance to antiproteasome inhibitors. Novel agents targeting the UPS have recently undergone clinical development, although the results in nonhematological tumors were disappointing. There is a need to define the role played by the proteasome in gastrointestinal tumors and how it can be targeted in a more selective and effective manner in the clinic.
Expert Commentary
Ubiquitin, UBL modifiers and the proteasome are key elements that control many vital processes involved in tumor progression. Bortezomib was the first proteasome inhibitor with proven clinical activity; however, proteasome inhibitors have appeared to have a limited efficacy in nonhematological tumors, despite a strong rationale for their use in solid tumors. The clinical activity of bortezomib in patients with advanced gastrointestinal malignancies is disappointing. A deeper knowledge of the molecular mechanisms that govern the UPS is needed to understand why tumor cells are able to bypass the inhibition of the proteasome. Furthermore, there is a clear demand for novel biomarkers that can help to predict the clinical outcome of patients treated with proteasome inhibitors. The combination of proteasome inhibitors with other anti-tumor strategies, mainly tyrosine kinase inhibitors, may serve to overcome resistance to antiproteasome inhibitors. Novel agents targeting the UPS have recently undergone clinical development, although the results in nonhematological tumors were disappointing. There is a need to define the role played by the proteasome in gastrointestinal tumors and how it can be targeted in a more selective and effective manner in the clinic.
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