ROTTWEILERUpdate - OSTEOSARCOMA RESEARCH A New Vaccine & Gene Expression Profiling - Purina Pro Club
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ROTTWEILER Update
A NESTLÉ PURINA PUBLICATION DEDICATED TO ROTTWEILER ENTHUSIASTS VOLUME 16 | SUMMER 2018
OSTEOSARCOMA
RESEARCH
A New Vaccine & Gene Expression Profiling
SUMMER 2018
ROTTWEILERS MAY BENEFIT FROM
ADVANCES IN
OSTEOSARCOMA RESEARCH
“Benelli,” or “Benny” for short, was panion Animal Hospital. Rottweiler
5 years old in 2007 when he was owners since 1988, they adored the
diagnosed with osteosarcoma in intelligence and versatility of the
his right front leg. The gregarious working breed. Benny, one of four
Rottweiler, titled in conformation, male Rotties who shared their home,
obedience, carting, and as a therapy had a special gift as a certified
dog, seemed to have a bum leg from reading education assistance dog.
A tough, complicated the start. At 18 months old, Benny, “We wanted to know what was
painfully lame, had surgery for going on with Benny’s leg,” says
cancer, no one knows elbow dysplasia. Kelly Skiptunas. “Benny was
When the lameness came back unbelievably smart and intuitive.
exactly what causes
three years later, owners Kelly and Everyone loved him. He loved all
osteosarcoma, and efforts Dr. Anthony Skiptunas of Wrightsville, people, especially children.”
Pennsylvania, took Benny to be Initially diagnosed with severe
to better understand the examined at Cornell University Com- osteoarthritis in his leg and elbow,
Benny, they learned a few months
cancer have been challenging. later, also had early-stage osteo-
sarcoma, a tiny lesion invisible on a
radiograph but apparent on a bone
scan. Their options were dismal.
A tough, complicated cancer, no
one knows exactly what causes
osteosarcoma. Standard treatment
for the aggressive, most common
bone cancer in dogs is amputation
of the affected leg followed by
chemotherapy to help reduce the
risk of metastasis. About 50 percent
of dogs receiving the standard
treatment survive nine to 11 months
after diagnosis and surgery, about
20 percent survive two years, and
about 5 percent survive three years.
When dogs are treated with ampu-
tation alone, the median survival
Kelly Skiptunas and “Benny” (AM/CAN is six to seven months. More than
CH Oakview’s Roughrider v Esmond RN,
CI, TT, CGC, RTD, TDI, R.E.A.D certified), 90 percent of dogs receiving no
wearing a brace on his front leg treated for treatment or alternative holistic
osteosarcoma, receive the American Kennel
Club’s ACE (Award for Canine Excellence)
treatments die from metastatic
Award for Pet Therapy in 2012. disease within three to five months.
2
ROTTWEILER Update
THINGS TO KNOW ABOUT
CANINE OSTEOSARCOMA
• It is the most common bone
cancer in dogs
• It can occur in any bone, but
the legs account for 75 to 85
percent of cases
• Virtually all dogs from large
A certified reading education assistance dog, Benny was adored by children because and giant breeds, as well as
he listened attentively and patiently as they practiced reading aloud. large and giant mixed-breed
dogs, are at greater risk for
Efforts to better understand “We didn’t want to amputate this disease
osteosarcoma have been challeng- his leg, he was so young,” Kelly • Signs include lameness, swelling
ing. Recent advances include a Skiptunas says. at the tumor site and pain
new canine osteosarcoma vaccine Post-surgical care involved Benny • Irritability, aggression, loss of
developed at the University of wearing an external fixator daily for appetite, weight loss, whimpering,
Pennsylvania that shows promise in two months. Every four hours, the sleeplessness, and reluctance
extending survival following surgery family adjusted the fixator to help to exercise often relate to pain
and chemotherapy. At the University stretch the bone so it would grow, • Standard treatment involves
of Minnesota, investigators are using and every night, Dr. Skiptunas amputation of the affected leg
gene expression profiling to help unwrapped the bandages and and chemotherapy
them understand the biological carefully cleaned the surgical site
behavior of osteosarcoma tumors. to reduce the risk of infection. Source: The National Canine Cancer
Insights may help them learn how Benny breezed through chemo- Foundation
quickly the disease progresses locally, therapy with no side effects and
how quickly it spreads to other sites, continued his important job at
and what factors may accelerate read-to-a-dog programs, where
or delay disease progression. children gathered around him to
Meanwhile, the surgery team at take their turns reading aloud. He
Cornell evaluated Benny’s case, and and Kelly Skiptunas also visited
determined he was an ideal can- hospitals, rehabilitation centers
didate for a limb-sparing surgery and assisted-living facilities.
known as longitudinal bone trans- When he was 10 years old in 2012,
port. The procedure removes the Benny became the first Rottweiler to
affected portion of the bone and receive the American Kennel Club’s
then forms new bone, or a free ACE (Award for Canine Excellence)
transport segment, via osteotomy, Award for Pet Therapy honoring
eventually fusing the defective his many contributions as a therapy
area with healthy bone. and reading education assistance
3
SUMMER 2018
dog. It was a proud day when he cells that remain in the body after
and Kelly Skiptunas received the standard of care treatment and
honor at the AKC National Cham- eliminate them, thus delaying or
pionship. Three months later — five preventing relapse.
years after being diagnosed with Listeria monocytogenes is a bac-
osteosarcoma — Benny passed terium that triggers a strong cellular
away from another, unrelated can- immune response. Although in people
cer, hemangiosacoma. unmodified Listeria can cause a
serious and sometimes deadly infec-
A PROMISING VACCINE tion when contaminated food is
Greater understanding about how ingested, the bacteria in this vaccine
tumors and the immune system has been genetically attenuated,
interact have contributed to the or weakened, so as not to cause
development of a promising osteo- infection or disease.
sarcoma vaccine immunotherapy, Explaining the rationale behind
“The Listeria vaccine says Nicola Mason, BVetMed, PhD, the vaccine, Dr. Mason says, “most
essentially wakes us the DACVIM, associate professor of dogs relapse with metastatic disease
medicine and pathobiology at the after chemotherapy, suggesting that
immune system and directs University of Pennsylvania. not all cancer cells are eliminated
A pilot study of 18 dogs treated by chemotherapy. The Listeria
it to specifically eliminate with a live recombinant, HER2- vaccine essentially wakes up the
the remaining tumor cells expressing Listeria (ADXS31-164) immune system and directs it to
vaccine showed it doubled the specifically eliminate remaining
by delivering a target tumor survival rate compared to an his- tumor cells by delivering a target
torical control group. The dogs in tumor molecule into the system.
molecule into the system.” the study had surgery to remove “Immune cells that have been
their primary tumor followed by educated by the vaccine will then
Nicola Mason, BVetMed, PhD, DACVIM,
four chemotherapy treatments, seek out cells that express the target
associate professor of medicine and
pathobiology, University of Pennsylvania
and then they received three doses molecule and specifically kill them.
of the vaccine every three weeks. Essentially, we are aiming to gener-
The median survival was 956 days ate an effective anti-tumor immune
compared to 423 days for the response.”
control group. A phase-two clinical trial, sponsored
Funded by Advaxis Inc., a human by Morris Animal Foundation, has
biotechnology company, the phase- begun at 11 university hospitals
one study conducted at the Univer- across the U.S. and Canada using
sity of Pennsylvania included two the ADXS31-164 vaccine. The study,
Rottweilers. “One was a 7-year-old performed through the Comparative
male and the other was a 6 1/2-year- Oncology Trials Consortium, aims
old bitch,” says Dr. Mason. “Both had to treat 80 dogs with the vaccine
forelimb lesions and underwent following standard of care amputa-
amputation, follow-up chemotherapy tion and chemotherapy and deter-
and then received the vaccine. Both mine whether these promising
dogs did very well; the male lived results are also seen in a larger
956 days following the vaccine group of dogs. The trial also aims
treatment, and the female lived to evaluate immune parameters
886 days.” that might predict “responders”
The vaccine uses a genetically versus “non-responders.”
modified Listeria to deliver a tumor- Aratana Therapeutics, a company
associated antigen to stimulate the that markets innovative therapies
immune system and activate cyto- for dogs and cats, has received a
toxic (killer) T cells. These killer T conditional license for a lyophilized,
cells specifically recognize cancer or freeze-dried, version of this vaccine.
4
ROTTWEILER Update
The company hopes to receive full
licensure in the next year. ROTTWEILERS WITH OSTEOSARCOMA MAY BE
To be eligible to participate in CANDIDATES FOR VIGOR TRIAL
the clinical trial, dogs cannot have
evidence of metastatic disease at A novel oncolytic immunotherapy for treatment of canine osteosarcoma
the time of amputation surgery. If is being investigated at the University of Minnesota. The study is
dogs develop metastatic disease designed to learn more about how well a genetically modified vesicular
during their chemotherapy and stomatitis virus (VSV) kills cancer cells.
before receiving the vaccine, owners Dogs chosen for the study will receive either the VSV treatment or
have the option of fast-tracking a placebo. Neither the owner nor the investigators will know which
their dog to receive the vaccine. treatment the dogs are given. Owners and dogs will benefit because
“About one-third of dogs develop the participants will receive the best available standard of care for this
metastasis before their fourth disease, including amputation of the affected leg and chemotherapy.
chemotherapy treatment,” says Additionally, advanced imaging studies will allow veterinarians caring
Dr. Mason. “By including the fast- for the dogs to determine disease progression at an earlier time when
track group in this study, we can other treatment alternatives still can be considered.
determine whether this approach To participate, owners must cover the cost of a screening appoint-
can delay the progression of grossly ment and diagnostics to determine if their dog is a good candidate
evident metastatic disease.” for the study. Once accepted, owners must be able to take their dogs
In addition to improving the for periodic recheck visits. The study covers up to $8,600 in care,
standard of care for dogs with which includes the VSV treatment, surgery and part of the costs for
osteosarcoma, the long-term goal chemotherapy.
of the University of Pennsylvania To be eligible, dogs must:
researchers is to learn whether the • Be diagnosed with osteosarcoma in a limb bone
same vaccine could be used to • Weigh more than 44 pounds
help children with bone cancer. In • Be healthy, with no significant health concerns
humans, the majority of osteosar- • Be spayed or neutered
coma cases occur in children. • Be current on vaccinations, flea and tick prevention, and heart-
“Taking a comparative oncology worm protection
approach, we believe that our canine • Have no evidence of metastasis on a chest X-ray
patients may help to guide a pediatric • Have had no previous treatment for their tumor
human clinical trial so we can learn For information about participating in the study, please contact
whether this approach might benefit Andrea Eckert, research study technician, at 612-625-3157 or
both species,” says Dr. Mason. aleckert@umn.edu.
A POTENTIAL CANCER
DIAGNOSTIC TEST
Cancer researchers at the Univer-
sity of Minnesota are working to
identify the molecular properties
of various tumor types, including
osteosarcoma, in an effort to gather
information that will help them
diagnose cancer risk and predict
disease behavior more accurately.
Their ultimate goal is to develop
effective strategies to treat and
eventually prevent osteosarcoma
in both dogs and children.
A recent University of Minnesota
osteosarcoma study, published in
the January 2018 issue of Cancer
Research, reported on evaluating
5
SUMMER 2018
the transcriptional profile of five-year survival for osteosarcoma
osteosarcoma tumors in dogs, is around 80 percent, and the 10-
humans and mice.1 Also known year survival is 50 to 60 percent.
as gene expression profiling, a “One of our goals has been to
transcriptional profile quantifies define peculiar genetic traits that
the abundance of messenger RNA may contribute to osteosarcoma
(mRNA) molecules for every gene in dogs and whether any of these
in cells or tissues. traits may also contribute to this
RNA, which is short for ribonucleic disease in people,” Dr. Modiano
acid, acts as a messenger in cells, explains. “Our present goal is to
transcribing genetic information understand how specific mutations
from DNA into amino-acid sequences help tumors mold their environment
that become the protein products and evade the immune system.
of gene expression. The differential Identifying such mutations, in dogs
“While the GCESS method patterns of gene expression in or humans, will help us develop tools
tumors from individual patients to diagnose the disease earlier when
was developed using allow researchers to categorize interventions are more likely to
osteosarcoma as a model, cancers, such as osteosarcoma, into produce long-term benefits and to
subgroups with different behaviors design effective strategies that are
we found it is widely and different prognoses. better tailored to each individual
The comparative medicine approach patient.”
applicable to virtually any used by the University of Minnesota The researchers used next-gen-
researchers, gleaning information eration sequencing to analyze all
type of tumor where
from dogs, mice and humans, of the mRNA in human, dog and
genome-wide sequencing provides opportunities to better mouse tumors. “Our hypothesis
understand osteosarcoma. The was that despite the highly com-
information can be obtained.” study team was made up of sci- plex karyotypes (chromosomal
entists with diverse backgrounds, variation) seen in osteosarcoma,
Jaime Modiano, VMD, PhD, the Perlman
including bioinformatics, genetics transcriptional profiles would allow
Endowed Chair of animal oncology,
and genomics, pathology, immu- us to categorize this cancer into
University of Minnesota
nology, molecular biology, cancer distinctive, clinically relevant sub-
biology, and stem-cell biology. types,” says Dr. Modiano.
One of the study investigators, Samples from newly diagnosed
Jaime Modiano, VMD, PhD, the human and dog osteosarcoma
Perlman Endowed Chair of animal patients that had not yet received
oncology at the University of any therapy were included in the
Minnesota, says, “Human, dog and study. The dogs’ samples came from
mouse osteosarcoma tumors share a large number of breeds, includ-
certain clinical and molecular simi- ing many Rottweilers and Golden
larities, but they also have import- Retrievers, obtained between 1999
ant species-specific differences. and 2012.
Insights gained from each species The most exciting development
help us improve our overall under- from the study was the creation of
standing of the disease.” the gene cluster expression sum-
A rare cancer in people, with mary score (GCESS) methodology
400 to 600 new cases diagnosed to categorize tumors. The GCESS
annually in the U.S., osteosarcoma captures information from many
is much more common in dogs. The genes that are turned on and off
small number of human tumors coordinately, likely by the same
available for study compounds the mechanisms, says Dr. Modiano.
ability of researchers to study the “Because of the sheer size of the
rare but deadly cancer. In children, clusters and their tight correlation,
adolescents and young adults, the the GCESS method is significantly
6
ROTTWEILER Update
more powerful to achieve
this classification than bio-
markers that use a single
or even a few genes or mol-
ecules,” he says. “While the
GCESS method was devel-
oped using osteosarcoma as
a model, we found it is widely
applicable to virtually any
type of tumor where genome-
wide sequencing information
can be obtained.”
Using the GCESS method,
the research team identified
three clusters that were
conserved across all three
species and that had clinical
significance in at least one
species. One cluster, discov-
ered by the team as part of
an earlier study, was strongly
associated with genes that
control cell division and DNA
repair. The investigators
confirmed their previous
observation that the relative
expression of this cluster
was highly predictive for
overall survival in dogs with
A conformation champion, Benny also was active in obedience, carting, and working as a
osteosarcoma independent therapy dog.
of treatment.
The other two clusters were Skiptunas says, “The surgery LOOKING TO REPRINT?
indicative of immune cells being doubled his life span. Now, looking
present within the tumor. “Inter- back at what we went through, I Rottweiler Update articles may
estingly, the relative abundance don’t know if we could do it again. be reprinted provided the article
of immune-cell transcripts was a I am so thankful for the extra years is used in its entirety and in a
strong predictor for outcome in we had with him. He was special positive manner. To request
human patients, but not in dogs with to us and to so many other people permission to reprint an article,
osteosarcoma,” says Dr. Modiano. through his gentle, unassuming please contact the editor at:
“The reasons for this are unclear, nature as a therapy dog.” n barbara.fawver@purina.nestle.
but they provide a stark illustration com. Reprints should include the
of species differences that must be 1 Scott MC, Temiz NA, Sarver AE, et al. following attribution: Used with
considered when dogs are used as Comparative Transcriptome Analysis permission from the Rottweiler
Quantifies Immune-Cell Transcript Levels,
models for human cancer causation Metastatic Progression and Survival in Update, Nestlé Purina PetCare.
or cancer treatments. Most impor- Osteosarcoma. Cancer Research. 2018;
tantly, these differences do not 78(2):326-337.
negate the utility of comparative
approaches. To the contrary, under-
standing these differences makes it Purina thanks Roberta Kelley-
possible to design better experiments Martin, president of the Rott-
and to obtain more robust answers.” weiler Health Foundation, for
helping us to identify this topic
Reflecting on her experience
for the Rottweiler Update.
with Benny’s osteosarcoma, Kelly
7
SUMMER 2018
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