Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 265

4.2 Limitations of Bevacizumab for Anti-Angiogenic Therapy
The limitations of bevacizumab became evident in clinical trials for metastatic
breast cancer. An open-label, randomized phase III clinical trial was conducted to
determine whether the addition of bevacizumab to paclitaxel is beneficial for
metastatic breast cancer therapy [ 66 ]. A total of 722 patients were enrolled in the
trial, and were randomized to receive either bevacizumab plus paclitaxel, or
paclitaxel alone. Initial therapy of metastatic breast cancer with bevacizumab plus
paclitaxel did prolong progression-free survival, as compared with paclitaxel
alone. However, bevacizumab imparted no benefits for overall survival in meta-
static breast cancer.
Bevacizumab also failed to demonstrate efficacy for pancreatic cancer.
A randomized, double-blinded phase III clinical trial was conducted in 301 patients
with metastatic pancreatic adenocarcinoma [ 67 ]. Patients were randomly assigned
to receive either bevacizumab plus gemcitabine-erlotinib, or gemcitabine-erlotinib
alone. The addition of bevacizumab to gemcitabine-erlotinib did prolong
progression-free survival, but there was no improvement in overall survival.
A subsequent phase III clinical trial was conducted in 602 patients with advanced
pancreatic cancer; patients were randomly assigned to receive bevacizumab plus
gemcitabine, or gemcitabine alone [ 68 ]. Again, there was no survival benefit
associated with the addition of bevacizumab to gemcitabine.
4.3 Tumor Resistance to VEGF-Blocking Agents
VEGF-blocking agents not only bear limitations with regard to efficacy, they can also
induce undesirable long-term effects. Notably, tumors can cultivate complete
resistance to anti-angiogenic VEGF-targeting agents over time, leading to tumor
resurgence. One mechanism for tumor resistance is the existence of alternative
angiogenic signaling pathways. Even when VEGF-mediated signaling is entirely
blocked, tumors can utilize other pro-angiogenic factors as substitutes for VEGF
[ 69 ]. As a case in point, inhibition of VEGF signaling in late-stage pancreatic islet
tumors leads to upregulation of other pro-angiogenic mediators, including molecules
of the FGF family [ 70 ]. Inhibition of VEGF-mediated pathways can even lead to
up-regulation of VEGF itself in glioblastoma multiforme [ 71 ]. Paradoxically,
VEGF-blocking therapeutic agents increase tumor hypoxia, which leads to the
activation of pro-angiogenic pathways. When malignant tumors are treated with
VEGF-blocking agents, the tumors initially respond to treatment and stop growing;
after this initial period of growth suppression, malignant tumors rebound aggres-
sively as they re-vascularize and relapse via multiple signaling pathways.
For patients fighting cancer, the clinical result is that anti-angiogenic therapies
have short-lived efficacy at best. Patients experience a transient clinical benefit,
followed by tumor re-growth at a greatly accelerated pace. Therapies such as
bevacizumab may effect a 3-6 month increase in progression-free survival, but