Novel Treatment Options for the Veterinary Cancer Patient
Chand Khanna, DVM, PhD,
DACVIM (Oncology)
The problem of cancer
Patients that present with metastatic disease or
those who develop metastases after successful
management of the primary tumor carry a
universally grave prognosis. Conventional
therapeutic options are poorly effective in most
cases. As such novel treatments for patients
with a risk for metastasis or for those who have
already developed metastases are needed. Our
understanding of the biology of metastasis has
expanded in recent years and is now shedding
light on novel treatment strategies for patients
with gross metastases and those with a high risk
of metastatic recurrence.
The Biology of Metastases
In order for a cancer cell to successfully
metastasize it must leave the site of the
primary tumor, pass through the tumor basement
membrane, and then through or between
endothelial cells to enter the circulation (extravasation).
While in the circulation tumor cells must be
able to resist anoikis (programmed cell death
associated with loss of cellular contact), evade
immune recognition and physical stress, and
eventually arrest at distant organs. At that
distant site the cell must leave the circulation
and survive in the hostile microenvironment of
the foreign tissue site. This distant site may
be the eventual target organ for metastasis or
may be a temporary site. In either case the
cancer cell is thought to lie dormant for a
protracted period of time before moving to its
final location. Following dormancy, the cells
receive signals to proliferate, create new blood
vessels (angiogenesis) or co-opt existing blood
vessels and then successfully grow into a
measurable metastatic tumor. It is likely that
further progression is associated with the
repetition of this process resulting in
metastases from metastases.
New Treatments Based on
an Improved Understanding of Biology
Through an improved understanding of the biology
of cancer metastasis, novel treatment approaches
are now commercially available, and others are
in clinical trials. This session will summarize
the newly available agents and the status of
agents still in the development process. No
matter how promising these treatments may be, it
is predictable that cancer cells will be able to
overcome each individual therapy. As such, it
will be important to define how these novel
treatments may best be used in combination with
conventional chemotherapy agents and with other
novel treatment agents. A discussion of specific
novel treatments agents for cancer is presented
with the relevant metastasis-associated process.
Extravasation/Invasion
Dissolving the
extracellular matrix is essential for cancer
cells as they initiate the metastatic process
within the primary tumor site and when cells
leave the circulation at distant metastatic
sites. This process of invasion is mediated by a
series of enzymes including matrix
metalloproteinases (MMP). Many commonly used
veterinary drugs inhibit MMP activity (i.e.,
doxycycline); however, agents specifically
designed to antagonize these enzymes have been
developed and evaluated in both human and
veterinary cancer patients. Most clinical
trials, in human patients, using MMP inhibitors
have not been successful. A failure to define
optimally effective doses and treatment
schedules, as well as unexpected toxicities
related to these MMP inhibitors may in part
explain their failures as drugs. Interestingly,
at doses well below those used in human clinical
trials, modest improvements in outcome were seen
in selected dogs with lymphoma entered to a
randomized, placebo blinded trial with a
selective MMP inhibitor in combination with
conventional chemotherapy. The improvement was
most evident in older dogs and dogs with the
highest pre-treatment MMP levels (Personal
communication G. Ogilvie).
Evade Immune Surveillance
The belief that
the immune system may play a role in the
treatment of cancer has been held for over 100
years. Coley, a surgeon in the early 1900s,
observed the spontaneous regression of bulky
tumors in women following bacterial sepsis. His
belief that the fever associated with sepsis was
responsible for regression of the tumors lead
him to administer mixtures of bacteria to
patients in the hopes of re-creating fever and
resultant tumor regression. These bacterial
mixtures, referred to as Coley's toxins, were
the first documented attempts at cancer
immunotherapy. Since the days of Coley,
considerable progress in our understanding of
the immune response (and lack of immune
response) against cancer has emerged. This
understanding may be summarized in the following
generalizations:
-
Cancers differ in their
sensitivity to immune recognition and
destruction (immunogenicity)
-
The determinants for immune
recognition of cancers are specific to each
cancer type
-
Cancers evade immune
recognition by many different mechanisms
-
The cell-mediated immune
response is important in generating immune
recognition of the cancer
-
Cancer immunotherapy is
likely to be most effective against small
tumor burdens
This understanding has lead to several promising
strategies that use the immune system to first
detect and then destroy cancer cells. Approaches
to immunotherapy include the following:
Non-specific Immunotherapy--where
bacterial agents (e.g., BCG, Corynebacterium
Parvum), natural products (Acemannan), synthetic
compounds (Muramyl tripeptide), chemical agents,
and others, are used to stimulate an immune
response. This approach is similar to that of
Coley, and is referred to as non-specific
because the target for immune recognition in the
cancer is not known. The most extensively
studied form of non-specific immunotherapy in
veterinary oncology is muramyl tripeptide (MTP).
In randomized, controlled, and placebo-blinded
trials, MacEwen et al have demonstrated
the activity of MTP against canine osteosarcoma
and canine hemangiosarcoma. Treatment of dogs
with osteosarcoma or hemangiosarcoma using MTP
plus chemotherapy resulted in significantly
longer survival times compared to chemotherapy
alone. There has been a renewed commercial
interest in the development of MTP by IDM,
who is considering the development of MTP for
pediatric osteosarcoma patients.
Specific Immunotherapy--attempts
to generate a specific immune response against a
known or unknown tumor antigen (target). A tumor
vaccine is the most common form of specific
immunotherapy. Our understanding of the immune
response against cancer suggests that the most
effective tumor vaccines will stimulate
cell-mediated responses against cancer. Clinical
trials using a number of vaccination approaches
are currently ongoing at several sites in the
United
States for dogs with melanoma,
osteosarcoma, and hemangiosarcoma. In some
cases, these treatment options do not require
travel to the sponsoring institution. More
information about these clinical trials can be
found at
www.vetcancersociety.org.
Adoptive Immunotherapy--refers
to the administration of parts of the immune
system to a patient. Monoclonal antibodies
raised against cancers represent adoptive
humoral immunotherapy. Advances in the design of
monoclonal antibodies to prevent immune
reactions against the antibody and to improve
antigen recognition have raised the potential
value of this type of therapy. The land-mark
approval of Herceptin®, an antibody that binds
the Her2/neu gene product, to treat breast
cancer in women is evidence of the progress that
has been made in this field. Since the approval
of Herceptin, a series of antibody-based
therapies have become available for the
treatment of cancer in human patients (e.g.,
Avastin, Erbitux, Rituxin). These treatment
approaches have received considerable press and
as such, interest from pet owners; however,
humanized monoclonal antibodies are not likely
to have wide application in the treatment of
canine or feline cancers since the development
of neutralizing antibodies against these human
proteins is likely to occur. Future development
of smaller fragments of antibodies, peptide
antibodies, may have greater transferability to
veterinary patients.
Cytokine Immunotherapy--refers
to the administration of products of the immune
system (cytokines) to stimulate or direct
anti-tumor immune responses. Cytokines are
released by leukocytes and function in the
activation and regulation of the immune
response. Cytokines, such as interleukin-2
(IL-2), have been used to induce significant
anti-tumor immune responses and objective tumor
responses in dogs with osteosarcoma. We have
shown in a small number of dogs with pulmonary
metastasis from appendicular osteosarcoma
(4/16), complete regression of metastases after
the inhalation IL-2. Interleukin-2 is
commercially available through most large drug
distributors. It is not likely that cytokine
therapy will become a single cancer treatment,
rather it is more likely that it will become
part of another immunotherapeutic approach
(i.e., used as a cancer vaccine adjuvant).
Information on the delivery of aerosols of IL-2
are available at :www.animalci.com.
Survival at Distant Sites
The ability of
cancer cells to survive in distant "foreign"
tissues immediately after arrest or while cancer
cells are in a dormant state is a hallmark of
successful metastasis. For most metastatic
cancers, this ability to survive is in part
regulated by internal genetic cues, but also by
signals received from the microenvironment
(growth factors). A number of small molecules
that inhibit signal transduction from growth
factor receptors have been developed as cancer
agents. Many of these agents may have a role in
treating metastases through the disruption of
critical survival signals provided by these
growth factor receptors. In work from London
et al, a small molecule inhibitor (SU11654)
of the split tyrosine kinase receptor family was
found to be active in a number of canine
cancers, including mast cell tumors, metastatic
sarcoma, and mammary carcinoma.
The split tyrosine kinase receptors that are
inhibited by SU11654 have a diversity of
biological effects. As such, their inhibition
may not be limited to preventing survival and
may be the result of the inhibition of many
steps in the metastatic cascade. As a class,
small molecular inhibitors of tyrosine kinase
receptors represent one of the most promising
types of novel therapies for cancer and cancer
metastases. Clinical trials using these agents
are underway at several veterinary referral
centers and veterinary teaching hospitals across
the United
States.
Angiogenesis
Angiogenesis
describes the generation or recruitment of new
blood vessels. It appears that new blood vessel
development is essential for tumor cells to grow
and metastasize. The new blood vessels may be
created by the tumor or may be recruited from
the surrounding normal tissues. If new blood
vessel formation or recruitment can be
inhibited, a tumor cannot progress and may cause
established tumors to regress. Therapies that
are directed against blood vessels and not tumor
cells are likely to be active against a wide
spectrum of cancers. Biological differences
between tumor associated endothelial cells and
normal endothelial cells have become apparent.
This has lead to several novel therapeutic
agents that either prevent new blood vessel
formation or survival (antiangiogenic agents),
or specifically target existing tumor-associated
blood vessels (vascular targeting agents).
Recent studies using antiangiogenic peptides of
thrombospondin-I (TSP-I) have demonstrated
surprising objective regressions of metastatic
cancers in dogs with a variety of histologies
and have significantly extended remission
duration in dogs with lymphoma when combined
with chemotherapy (demonstrated in a randomized
controlled trial). Trials with TSP-I peptides in
dogs are underway at several sites across the
United
States.
Progress that has been made in our understanding
of the basic biology of cancer has uncovered
several opportunities for the treatment of
cancer. The improved knowledge of cancer biology
has allowed differences between cancer cells and
normal cells to be identified and has uncovered
important interactions that occur between cancer
cells and the host. The cancer treatment
strategies discussed above specifically target
cancer, and as such are less likely to result in
the toxicities that are associated with
conventional cancer therapy. Effective and
non-toxic cancer therapy is therefore the goal.
In the very near future, we can expect these
novel treatments to be used in conjunction with
conventional cancer treatment modalities
(surgery, radiation therapy, and chemotherapy)
in the management of our veterinary cancer
patients.
A New Option for the Treatment of Canine Lymphoma
This article is a wonderful one as Dr.
Khanna is doing some of the leading nationwide
canine cancer research.
Tales of the 'Trojan horse drug' and the 'miracle dogs'
The
American Chemical Society
SALT LAKE CITY, March 23, 2009 — Diagnosed with an extremely aggressive form of
cancer called anal sac adenocarcinoma, Oscar's future seemed bleak. Bedridden
and unresponsive to chemotherapy or radiation, he would be lucky to survive
three months. But thanks to an innovative new drug treatment, Oscar's cancer
receded and he was walking again within two weeks.
Oscar's recovery was extraordinary enough, but his case was unusual for another
reason. Oscar is a Bichon Frise, who scientists reporting here today at the
237th National Meeting of the American Chemical Society call "the Miracle Dog."
Joseph A. Bauer, Ph.D., and colleagues described promising results with a drug
called nitrosylcobalamin (NO-Cbl) in battling cancer in Oscar and three other
canines without any negative side effects. While it gives profound hope to dog
owners, NO-Cbl also points to a powerful new cancer treatment for humans — one
that infiltrates cancer cells like a biological Trojan horse.
"We are one of the few research groups that is offering to treat dogs with
cancer that otherwise have no hope," Bauer said. "With no other options
available, most people in this situation opt to euthanize so that their pets
don't go through the pain of disease and trauma of surgery."
About six million dogs are diagnosed with cancer each year in the United States.
According to the National Cancer Institute (NCI), pets with cancer provide a
win-win opportunity for cancer researchers. Scientists can study new cancer
treatments in animals other than lab mice. And pets get access to new treatments
that provide hope and in instances like NO-Cbl, additional time.
Bauer put it this way: "The beauty of using a dog or a cat to test a cancer drug
is two-fold. First, the animal can get the benefit of the most up-to-date drug
in cancer medicine. Second, the NCI gets data on pets that are exposed to the
same environmental factors their owners are. They breathe the same polluted air
and drink the same polluted water that you and I do every day. If you can find
an agent to treat cancer that occurs in a dog with success, there is a higher
likelihood that you can take that to the human population and have a much higher
response rate than with mice."
Although NO-Cbl has been used in only a few dogs, daily treatments have led to
promising results in each case. "In all four dogs, there has been a significant
reduction in tumor size without any toxic side effects or discomfort," says
Bauer.
Oscar was the first success story. Since then, Bauer has treated two other dogs.
A six-year old golden retriever named Buddy was unable to walk due to a spinal
tumor pinching essential nerves leading to his right hind leg. After nine months
of daily NO-Cbl treatment, Buddy's tumor shrank by 40 percent and he was going
on two mile walks. A 13-year-old female Giant Schnauzer with inoperable thyroid
carcinoma also showed tumor reductions of 77 percent in less than 10 weeks.
"Our case studies demonstrate anti-tumor efficacy with limited toxicity to
normal tissues," Bauer added. "NO-Cbl sensitizes multidrug-resistant cancer
cells to the antitumor effects of several different drugs, so it may be valuable
when utilized in combination regimes," he added.
The drug targets cancer cells with "biological Trojan horse technology." Cells
have receptors for vitamin B12 on their outer surface. The receptors serve as
docking ports where molecules of the vitamin, essential for cells to divide and
multiply, attach and then enter the cell. In order to divide at their abnormally
rapid pace, cancer cells grow extra B12 receptors — 100 times more than normal
cancer cells. Scientists have been trying since the 1950s to exploit that
vulnerability and make B12-based drugs that attach to the receptors, sneak into
the cell, and deliver a knock-out dose of medication.
Bauer and his colleagues from the Cleveland Clinic attached nitric oxide (NO)
molecules to vitamin B12. NO kills cancer cells. The B12 acts as the Trojan
horse, easily slipping into cancer cells. The subsequent release of toxic NO
kills the cancer cells from within.
The team's goal is to successfully treat 10 dogs with NO-Cbl and slingshot the
drug into human use as soon as possible. Because of the genetic similarity
between dogs and humans, Bauer says his approach should have a much better
chance of getting through the FDA's strict drug approval chain.
But Bauer stresses he wants to get the NO-Cbl dog treatment approved, as well.
"I'm committed to the animals, and my goal would be to do a dual clinical trial,
Phase One human and Phase One dog," says Bauer.
Oscar is still alive and well. Today, Bauer is treating another Golden Retriever
named Haley with a spinal tumor.
"This is one of the most rewarding things I've ever done in my life," says
Bauer, the owner of a two-year old Beagle. "It gets boring working in the lab,
but to see the fruits of your labor in a positive outcome like this and to know
you're responsible in some small way, that's pretty cool."
—
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