Page 284 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 15 Molecular/Targeted Therapy of Cancer 263

dogs and cats, although it is not currently approved by the US number of proangiogenic growth factors and signaling pathways
FDA. In dogs with MCTs, MAS significantly improved time to promote the process of blood vessel growth. 186 Similarly, endog-
enous inhibitors of angiogenesis are temporally expressed to sup-
progression compared with placebo, and outcome was improved
VetBooks.ir in dogs with MCT harboring KIT mutations. 176 Subsequent press vessel expansion and maintain angiogenic balance. 189 The
net effect depends on this relative balance, which is tipped toward
follow-up of patients treated with long-term MAS identified an
increased number of patients with long-term disease control com- promoting angiogenesis during tumor growth. Therapeutic inter-
pared with those treated with placebo (40% vs 15% alive at 2 ventions aim to tip the scales back toward inhibiting angiogen-
years). 177 Small studies have also evaluated the efficacy of imatinib esis. 190 Importantly, the vessels produced to support tumor growth
for the treatment of canine and feline MCT. 178–180 Imatinib was are vastly different from normal vasculature. Tumor vessels are
well tolerated, and objective antitumor responses were observed in characterized by profound leakiness and sparse intermittent cover-
dogs with both mutant and wild-type KIT. Responses have also age of the endothelium by structural mural components, such as
been observed in cats with MCT. 181,182 pericytes. These abnormalities inherent in tumor vessels contribute
Other small molecule inhibitors are currently under develop- to the poor perfusion and high interstitial fluid pressure that are
ment for the treatment of canine cancer. RV1001 is an orally bio- consistent features of the tumor microenvironment.
available PI3Kδ inhibitor that has demonstrated significant activity “Classical” angiogenesis occurs through the sprouting of
against naïve and relapsed T- and B-cell lymphomas in dogs. In new vessels from existing vasculature. The term vasculogenesis
phase I and II clinical trials, objective response rates ranged from describes the de novo formation of new blood vessels from bone
62% to 77% (respectively), with hepatotoxicity as the primary marrow–derived progenitor cell populations that respond to
dose limiting event. 183 Verdinexor (KPT-335) is an orally bioavail- locally produced proangiogenic signals. 191,192 Numerous cell types
able small molecule inhibitor of XPO-1, a nuclear export protein that originate from bone marrow, including circulating endothe-
shuttle responsible for transporting several tumor suppressor pro- lial progenitor cells (CEPs), may contribute to tumor angiogenesis
teins, thereby extinguishing their function. Blockade of XPO1 by traveling to tumor sites and incorporating into existing vessel
forces retention of these proteins, including such key cellular regu- walls. 193–196 Finally, in certain circumstances, cancer cells may also
lators as p53, p21, RB, FOXO, and NFκB. Verdinexor has been access a blood supply through means other than sprouting new
evaluated in both phase I and II studies in dogs with lymphoma; vessels. In certain highly vascular tissue environments, cancers
objective response rates in both studies were approximately 35%, may use vessel co-option to grow along existing blood vessels, which
with several dogs experiencing long-term stable disease, and hypo- may ultimately lead to vessel collapse as the tumor grows. 197 In
rexia was determined to be the dose-limiting toxicity. 184,185 other contexts, cancer cells may produce microvascular chan-
nels that conduct fluid through a tumor cell–lined network in a
Conclusion process first described in uveal melanoma, known as vasculogenic
mimicry. 197,198 The relative contributions of classical angiogenesis,
With the advent of molecular techniques, the characterization of CEP contribution, vessel co-option, and vasculogenic mimicry are
signal transduction pathways that are dysfunctional in cancer cells likely cancer cell, organ/tissue environment, and stage dependent,
has become commonplace. Advances in computer modeling and potentially evolving as the tumor mass grows and becomes more
small molecule engineering have led to the rapid development of heterogeneous and therapy resistant.
inhibitors capable of blocking specific pathways critical for can- In addition to blood vessels, lymphatics are important compo-
cer cell proliferation and survival. The success of kinase inhibitors nents of the tumor microenvironment and a prominent feature of
such as imatinib and crizotinib indicate that the application of this tissue homeostasis, immunosurveillance, and a gateway to meta-
therapeutic strategy can markedly improve clinical outcomes. Per- static spread. 199 Lymphatic vessel growth regulation is physiologi-
haps the greatest challenges will be determining how these novel cally similar in principle to that of blood vessels, 200 and therefore
therapeutics can be effectively combined with standard treatment targeting lymphangiogenesis may also represent an attractive treat-
regimens such as surgery, chemotherapy, and radiation therapy to ment strategy in clinical oncology worthy of focused research. 201
provide optimal anticancer efficacy without enhancing toxicity,
and identifying strategies to use these therapeutics that are less Antiangiogenic Therapy
likely to result in drug resistance.
Angiogenesis became a validated therapeutic target in oncology
SECTION C: ANTIANGIOGENIC AND with the widespread approval of drugs that inhibit a potent sig-
naling pathway for blood vessel growth, the vascular endothelial
METRONOMIC THERAPY growth factor (VEGF) receptor tyrosine kinase pathway. 202–206
Drugs such as bevacizumab (Avastin), the humanized anti-VEGF
monoclonal antibody, and small molecule receptor tyrosine kinase
ANTHONY J. MUTSAERS AND inhibitors (RTKIs) such as sunitinib (Sutent) in human oncology
BARBARA BILLER and TOC phosphate (Palladia) in veterinary medicine are consid-
ered to be efficacious, at least in part, because of the antiangio-
Tumor Angiogenesis genic effects of VEGFR signaling inhibition. 207,208
Multiple mechanisms have been proposed to explain the anti-
For a solid tumor to grow beyond a few millimeters in size, it must tumor effects of antiangiogenic therapies. 204 The first and most
recruit a blood supply to provide adequate nutrients and oxygen to intuitive is vascular collapse resulting in impaired oxygen delivery
the dividing cell mass and remove waste products. 186,187 Inducing to the tumor, leading to nutrient starvation, hypoxia, and death
angiogenesis is a hallmark of cancer progression, 188 yet angiogen- of cancer cells that cannot survive in this environment. 209 Con-
esis is also a prominent aspect of normal physiology and transient versely, a second perhaps paradoxical mechanism involves more
pathology (e.g., in wound healing) and is tightly regulated. A large efficient delivery of oxygen, nutrients, and indeed other drugs