Page 285 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

264 PART III Therapeutic Modalities for the Cancer Patient

(such as chemotherapeutics) to tumor cells by the process of vessel sarcoma. 228 Results of a prospective randomized placebo-con-
normalization. 210,211 Normalization occurs when smaller, tortu- trolled clinical trial in dogs with multicentric lymphoma treated
at first relapse revealed significantly improved time to tumor pro-
ous, inefficient, and leaky tumor vessels are selectively destroyed
VetBooks.ir by the therapy, resulting in improved blood flow through more gression and remission duration, but not remission rate, when
ABT-526 was used in combination with lomustine chemother-
established vasculature, increasing perfusion to the tumor as a
whole. 212 Vascular normalization has been demonstrated clinically apy, compared with dogs treated with lomustine alone. 229 No
using functional magnetic resonance imaging (fMRI) in patients ABT-526–specific toxicities were noted in this trial. In addition
treated with VEGF pathway inhibitors. 213,214 The most common to thrombospondin-1, preliminary studies documenting detec-
clinical approach to targeting tumor angiogenesis has been either tion of the endogenous inhibitors angiostatin and endostatin in
inhibition of overexpressed proangiogenic stimuli or supplemen- normal and tumor-bearing dogs have been reported. 230,231 In a
tation of factors that inhibit angiogenesis, to tip the overall bal- pilot study of endostatin as a therapeutic agent, 13 dogs with
ance in favor of suppressing vessel growth. soft tissue sarcomas were treated with the canine endostatin gene
delivered via liposome–DNA complexes. 232 Although endostatin
Inhibition of Proangiogenic Factors gene expression was not detected in the tumors after treatment,
objective responses were documented in two dogs, and eight dogs
Currently, most RTKIs target numerous receptors to varying experienced stable disease, suggesting potential nonspecific anti-
degrees. 208,215 TOC is an example of an RTKI that complements tumor activity.
its direct effects on tumor cells (e.g., via mutated c-kit inhibition)
with angiogenesis inhibition because it directly targets VEG- Targeting Tumor Endothelial Cell Markers
FRs. 216 In addition, drugs that inhibit PDGFRs, such as TOC,
disrupt signaling pathways important for blood vessel support Tumor endothelial cells (ECs) differ from normal endothelia in
structures, such as the stromal pericyte component of larger ves- their gene and protein expression. 233 These differences may repre-
sels. 217,218 These drugs need not necessarily be purely antiangio- sent an opportunity for a favorable therapeutic index when drugs
genic, as blood vessel receptors such as VEGFR and PDGFR may are designed to bind differentially expressed targets on tumor-
also be expressed by certain cancer cells, resulting in an autocrine specific endothelium. If not naturally destructive to these cells,
growth factor loop within the tumor. 219,220 The end result is that, drugs can be designed to carry a payload to induce local cytotoxic-
in specific instances, targeting angiogenic pathways may have con- ity, producing an antiangiogenic effect. A phage vector delivering
current direct antitumor cell and antiangiogenic effects. tumor necrosis factor-alpha (RGD-A-TNF) to αV integrins on
Significant cross-influence exists between growth signaling tumor endothelium is an example of this strategy that has under-
pathways, and as a result there is strong interaction between gone evaluation in dogs. 234 Through serial biopsy, this dose escala-
tumor oncogene and suppressor gene expression and regulation tion trial demonstrated selective targeting of tumor endothelium
of blood vessel expansion through growth factors such as VEGF. via αV integrin-targeted expression of TNF, and treatment of
Therefore many drugs that target oncogenes have demonstrated a cohort of tumor-bearing dogs at the MTD resulted in partial
antiangiogenic “off-target” effects as a byproduct of VEGF reduc- remission in 2 of 14 and stable disease in 6 of 14 dogs.
tion. 221–223 For example, the anti-HER2 (ErbB-2) human MAb
trastuzumab (Herceptin) and anti-EGFR antibodies such as Other Antiangiogenic Agents
cetuximab (Erbitux) are examples of drugs that indirectly suppress
angiogenesis because neutralization of their oncogenic targets A vast array of drugs not necessarily designed as anticancer thera-
leads to a dramatic reduction in tumor cell VEGF production, peutics may derive at least a portion of their activity through inhi-
which increases again at the time of targeted drug resistance. 224,225 bition of angiogenesis. Two examples investigated in a veterinary
Through reduction in VEGF or other growth factor expression, setting include inhibitors of matrix metalloproteinases (MMPs)
there is an antiangiogenic component to many forms of cancer and cyclooxygenases (COXs). The MMPs are a family of enzymes
treatment, including not only targeted inhibitors but also cyto- that degrade the extracellular matrix and basement membrane,
toxic chemotherapy and RT. Therefore antiangiogenic effects thereby mediating tumor invasion, angiogenesis, and metas-
are not necessarily restricted to treatment modalities that target tasis. 235 Unfortunately, clinical evaluation of compounds that
known angiogenesis pathways directly. inhibit these enzymes has to date been largely unrewarding, 236,237
including results from a large randomized trial of 303 dogs with
Angiogenic Inhibitor Supplementation OSA, in which treatment with the MMP inhibitor Bay12-9566 or
placebo after doxorubicin (DOX) chemotherapy did not improve
Since the discovery of endogenous proteins and protein frag- overall survival. 238 Inhibition of the proinflammatory COX
ments that inhibit blood vessel growth, such as angiostatin, end- enzymes has been reported in numerous tumor types in veterinary
ostatin, and thrombospondins, there has been clinical interest oncology. 239–241 The effects of COX inhibition on angiogenesis
in using angiogenesis inhibitors as cancer therapeutics. 189,226 In were evaluated with piroxicam treatment of canine transitional
veterinary medicine, thrombospondin-1 mimetic peptides were cell carcinoma (TCC). In a study of 18 dogs, piroxicam treatment
evaluated in dogs with multiple tumor types. Treatment with was associated with reduced urinary concentrations of the pro-
the mimetic peptides ABT-526 and ABT-510 in a prospective angiogenic growth factor basic fibroblast growth factor (bFGF)
clinical trial of 242 dogs with multiple tumor types showed an and induction of apoptosis. 242 In a subsequent study evaluating
objective response or substantially stabilized disease in 42 dogs these parameters in 12 dogs treated with piroxicam in combina-
and a lack of dose-limiting toxicity. 227 Interestingly, most objec- tion with cisplatin, reductions in urinary bFGF and VEGF were
tive responses were recorded after 60 days of continuous drug associated with response to the combination regimen. 243
treatment. Subsequently, an updated formulation, ABT-898, Another agent with demonstrated antiangiogenic effects, tha-
demonstrated a response rate of 32% in 28 dogs with soft tissue lidomide, has been approved for treatment of human multiple