Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18)

Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment. Acquired drug resistance of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers. ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact. Each EC of a tumor vessel helps provide nourishment to many tumor cells, and although tumor angiogenesis can be driven by a number of exogenous proangiogenic stimuli, experimental data indicate that at least in some...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18) Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesismay provide unique opportunities for cancer treatment. Acquired drug resistanceof tumor cells due to their high intrinsic mutation rate is a major cause oftreatment failure in human cancers. ECs comprising the tumor vasculature aregenetically stable and do not share genetic changes with tumor cells; the ECapoptosis pathways are therefore intact. Each EC of a tumor vessel helps providenourishment to many tumor cells, and although tumor angiogenesis can be drivenby a number of exogenous proangiogenic stimuli, experimental data indicate thatat least in some tumor types, blockade of a single growth factor (e.g., VEGF) mayinhibit tumor-induced vascular growth. Angiogenesis inhibitors function bytargeting the critical molecular pathways involved in EC proliferation, migration,and/or survival, many of which are unique to the activated endothelium in tumors.Inhibition of growth factor and adhesion-dependent signaling pathways can induceEC apoptosis with concomitant inhibition of tumor growth. Different types oftumors use distinct molecular mechanisms to activate the angiogenic switch.Therefore, it is doubtful that a single antiangiogenic strategy will suffice for allhuman cancers; rather, a number of agents will be needed, each responding todistinct programs of angiogenesis used by different human cancers. Four randomized phase III clinical trials have demonstrated that theaddition of bevacizumab (Avastin; a humanized monoclonal antibody that bindsand inhibits VEGF) to chemotherapy results in significantly improved responserates, progression-free survival, and overall survival when compared to treatmentwith chemotherapy alone (Table 80-3). This effect was shown in the first-linetreatment of patients with advanced colon, lung, and breast cancers, and in thesecond-line treatment of colon cancer. However, not all trials have been positive;in previously treated breast cancer, the addition of bevacizumab to capecitabine(an oral fluoropyrimidine) did not increase efficacy, and in previously untreatedpancreatic cancer, bevacizumab did not enhance the efficacy of gemcitabine. Table 80-3 Randomized Phase III Clinical Trials Demonstrating theEfficacy of Bevacizumab in Combination with Chemotherapy for theTreatment of Advanced Cancers Tu Stage Previ Num Chemothe Outcmor Type of Disease ous ber of rapy Regimen ome Treatment Patients Col Metas No 813 Irinotecan Increon cancer tatic + 5-FU/LV ± ased OS bevacizumab (20.3 vs 15.6 months), PFS (10.6 vs 6.2 months), and RR (44.8 vs 34.8%) Col Metas Seco 829 FOLFOX Increon cancer tatic nd line; ± bevacizumab ased OS previous (12.9 vs 10.8 irinotecan/5 months), -FU PFS (7.2 vs 4.8 months), RR (21.8 vs 9.2%). Non Metas No 878 Carboplati Incre-small cell tatic num + paclitaxel ased OSlung ± bevacizumab (12.5 vs 10.2cancer months),(excluding PFS (6.4 vssquamous 4.5 months),histology) RR (27.2 vs 10.0%). Bre ...