NcXHF

KNAPP, DHAWAN, AND OSTRANDER
TABLE 1. Breed-Associated Risk for iUC in Dogs
Identified in Analyses of Veterinary Medical Data
Base Records
Breed
OR Compared
with Mixed Breed 95% CI
Mixed Breed Dog (Reference Category) 1.0 NA
Scottish Terrier 21.12 16.23-27.49
Eskimo Dog 6.58 3.34-12.96
Shetland Sheepdog 6.05 4.76-7.69
West Highland White Terrier 5.84 4.23-8.08
Keeshond 4.26 2.25-8.07
Samoyed 3.43 1.81-6.49
Beagle 3.09 2.34-4.08
Abbreviations: OR, odds ratio; NA, not applicable.
Records from Participating Veterinary Colleges in the United States and Canada of dogs
with iUC and dogs in the same breed without iUC (SNOMED search, 1999-2010).
One of the most powerful aspects of the naturally occurring
dog model for iUC is the strong breed-associated risk for the
cancer in dogs. There are at least seven breeds of dogs in
which the risks of iUC is over 3 times that of mixed breed
dogs, with the most impressive risk being in Scottish Terriers
(odds ratio [OR] 21.1; 95% CI, 16.23 to 27.49; Table 1).
GWAS have been used to identify two loci with strong significance
for iUC risk in dogs, and steps to elucidate the specifıc
genes involved are underway (E. Ostrander, H.G. Parker,
D.W. Knapp, unpublished data 2015).
The strong breed-associated risk can be used to select
groups of dogs for the study of iUC screening, early detection,
and early intervention. A study is underway in Scottish
Terriers in which a minimum of 100 dogs over the age of 7
who have no current evidence of bladder disease and no history
of bladder cancer will be monitored for at least 3 years.
The study calls for evaluation at 6-month intervals with medical
history, physical exam, ultrasound exam of the urinary
tract, urine sediment exam, and multiple emerging urinebased
assays to detect iUC. The goals of the study are to determine
the percentage of dogs in which cancer or precancer
(urothelial dysplasia, carcinoma in situ, and early-stage iUC)
can be found before the onset of any clinical signs of disease,
and to determine the appropriate screening interval, screening
test, and age to begin screening. Dogs with evidence of
cancer or precancer will undergo cystoscopy and biopsy.
Those with precancer or early-stage cancer will be eligible to
enroll in a secondary cancer prevention trial, with secondary
prevention being an intervention implemented at the earlystage
of cancer development to cause regression or to prevent
progression. In this particular study, the secondary prevention
agent being evaluated is a cyclooxygenase inhibiting
drug. With the compressed aging in dogs, this 3-year study in
dogs would be expected to be equivalent to an approximately
20-year study in humans. The expectation was that over a
period of 3 years, precancer or cancer would be found in approximately
30% of the dogs. With the study still in its fırst
year, however, the frequency of precancer and cancer detection
is much higher than expected at this time point. And,
with the cancer being found early, the antitumor effects of the
cyclooxygenase inhibitor are also exceeding that typically observed
in more advanced disease. It is anticipated that the
treatment response with nontargeted approaches such as cyclooxygenase
inhibitors, and to perhaps a greater extent with
targeted agents, will be better in early cancer that has not acquired
as many genetic changes leading to drug resistance.
This is encouraging evidence that this approach is one that
can be used to test current and future strategies for detection
and early intervention of iUC. It is exciting to consider that
dog studies, which are much quicker and much less expensive
to perform compared with human studies, could be used
to help design the approach with the highest likelihood of
success for the lengthier and far more costly human trials.
CHALLENGES TO ADVANCING CANCER RESEARCH
IN PET DOGS
Although there is substantial evidence for the value of pet dog
studies in cancer prevention and treatment research that
could positively effect human patients with cancer, there are
challenges that need to be met to make the most use of this
approach. There are at least three main areas where challenges
must be met: (1) funding, (2) critical mass of veterinary
scientists doing translational research, and (3) access to
appropriate numbers of dogs for clinical studies. Regarding
clinical research costs, dog trials are far less expensive than
human trials. For example, an appropriately powered, randomized
three-arm treatment trial in dogs, depending on the
intervention being tested and numbers of dogs needed, could
cost $1 million, whereas a similar study in humans would
cost $10s of millions to over $100 million. Thus, one could
clearly argue that if the dog study yielded results that were
then used to markedly increase the odds of success in the human
trial, that the dog study would be a very sound fınancial
investment. All too often, however, when funding agencies
and industry see that in some instances an entire mouse study
could be done for the costs of one to two of the dogs in a trial,
then the funding decisions go to the more traditional rodent
experiments rather than the dog study. Part of this is because
there has not been a “walk-off home run” in comparative oncology
research in the last 20 years, in which the dog study
was done fırst and the results clearly informed the design of a
follow-up human study that was successful because of the
dog work. There are numerous areas where translational researchers
are on the brink for work that should have this high
level of effect, but until that happens, funding agencies continue
to opt for more traditional animal studies, even if those
studies lack relevance to the human condition. Without
funding for dog studies, however, the “walk-off home run”
study is diffıcult, if not impossible, to achieve.
Another essential component of valuable translational research
utilizing pet dogs is the scientists that will drive the
work. The number of veterinary scientists with the knowledge,
experience, translational mindset, willingness to conduct
prospective clinical trials, and that make comparative
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