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Lymphoma’s Newest Enemy

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Posted By Nancy Kay D.V.M

In Canine Health

For the first time in a very long time, a new drug has been approved for dogs with lymphoma. The drug is called Tanovea-CA1 and it is produced by VetDC Inc., a startup company associated with Colorado State University. Earlier this month, Tanovea-CA1 received conditional approval from the Food and Drug Administration for treatment of dogs with lymphoma.

What is lymphoma?

Lymphoma is one of the most commonly diagnosed forms of cancer in dogs. Golden Retrievers are the unfortunate poster-puppies for this disease. Lymphoma arises from lymphocytes, normal white blood cells involved in the immune system. In dogs, lymphoma most commonly arises within the lymph nodes, spleen, and bone marrow, but because lymphocytes circulate virtually everywhere, it makes sense that lymphoma can grow anywhere within the body.

Lymphoma cells tend to be quite responsive to chemotherapy and radiation therapy, and it’s not unusual to achieve complete remission (no obvious trace of the cancer remaining) in response to treatment. What is very rare, however, is for lymphoma to be cured. Invariably, there is relapse of the cancer. While “rescue chemotherapy protocols” are often capable of zapping the cancer back into remission, over time those crafty lymphoma cells figure out how to develop significant drug resistance. With rare exception, lymphoma is a terminal disease.

Tanovea-CA1

The active ingredient in Tanovea-CA1 is rabacfosadine, first developed for use as a cancer-fighting drug in people. In dogs rabacfosadine has been documented to have anti-tumor activity in “naïve” lymphoma patients (those who have not yet been treated) as well as in those with a relapse of their cancer following treatment with other chemotherapy drugs. Tanovea-CA1 is an every-three-week treatment administered intravenously for up to five dosages. For now, Tanovea-CA1 has received “conditional” FDA approval, meaning it can be given to a dog for up to one year. The conditional approval may be extended with ongoing evidence of effectiveness.

How does Tanovea-CA1 compare?

The gold standard treatment for canine lymphoma utilizes a drug called doxorubicin that is often combined with three other drugs (cyclophosphamide, vincristine, and prednisone) in what is called a CHOP protocol.

In a study combining Tanovea and doxorubicin in 54 dogs with lymphoma, an 81% positive response rate was observed. This Tanovea/doxorubicin one-two punch was found to be generally safe and well tolerated.

The rate of response and duration of remission using the Tanovea/doxorubicin combination were both comparable to CHOP regimen results. Here’s the big difference. The CHOP protocol typically requires 12 to 16 treatment visits to complete. The Tanovea/doxorubicin treatment protocol was accomplished in only six visits. What a monumentally positive difference this would make, not only for the dogs, but for their human companions as well. I don’t yet know how pricing of the two protocols compares.

From my point of view, this is really great news on the canine lymphoma front. I’m on board with anything that makes effective treatment of this disease more efficient and less taxing for everyone involved.

When the Diagnosis is Cancer

The month of May has been declared Pet Cancer Awareness Month. While I’m not altogether sure who determines such things, in honor of this declaration I present to you a good deal of information that I’m certain will be useful should your four-legged family member develop cancer.

Cancer, neoplasia, growth, tumor, malignancy, the big “C”: no matter which word is used, it is the diagnosis we all dread. It’s not that cancer is always associated with a terrible outcome. What is true, however, is that whenever cancer is diagnosed, it is inevitable that lives are going to change. And change such as this isn’t something we relish when it comes to our pets.

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If your veterinarian suspects or knows that your pet has cancer, you will be asked to make a number of significant decisions. Some of them may have to do with diagnostic testing and others will pertain to treatment options. Such decisions can be tough in the best of times. If you’ve just learned your dog or cat has cancer, these decisions can feel downright overwhelming. What can you do to regain some control over the situation? Here are some suggestions.

Ask your veterinarian how urgently your decisions must be made. An extra day or two can make a huge difference in terms of settling down emotionally and doing the research needed to deal with the decisions at hand.

Do your best to put away preconceived, inaccurate notions of what you imagine your pet’s experience will be like. People often get sick, develop profound fatigue, and lose their hair in response to cancer therapy. It is uncommon for dogs and cats to experience such side effects.

Read, “surf,” and ask lots of questions. The more you learn about your pet’s cancer, the more you will feel empowered to make good decisions on their behalf. When researching via the Internet, be sure to surf responsibly. No sense wasting time on useless information.

Take things one step at a time. Being asked to make decisions for your dog with cancer is akin to climbing a tall mountain. It’s strategically and psychologically important to break your ascent into small manageable increments (and there’s less likelihood of tripping and falling when your eyes are not glued to the summit). Similarly, it is easier when you focus your attention on the medical decisions at hand rather than those that may (or may not) arise later.

Follow your own heart. Steer clear of folks intent on convincing you that he is “just a dog” or “just a cat,” and that the appropriate treatment is to “put the poor thing out of his misery.” Likewise, avoid those people who think that all animals must be treated as aggressively as possible for anything and everything. Wear a thick skin around such “influential” people (maybe take a sabbatical from socializing with them). Surround yourself with people who are open-minded and are interested in supporting rather than influencing you. Remember, you know better than anyone else what is right for yourself and your best buddy.

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Transitional Cell Carcinoma in Dogs

Transitional cell carcinoma (TCC) is the most common cancerous condition affecting the urinary tract of dogs. Scottish Terriers top the list in terms of breed predisposition.

What is TCC?

TCC is a malignant tumor that most commonly grows within the urinary bladder. It also frequents the urethra, the tube-like structure that drains urine from the bladder to the outside world. TCC can also arise within the prostate gland (males), kidneys, and ureters (the long, narrow tubes that transport urine from the kidneys into the bladder).

TCC arises from transitional epithelial cells that line the inner surface of the urinary tract. In addition to growing inward within the lumen of the bladder and/or urethra, the cancer cells invade locally into the walls of these structures. TCC cells also have the ability to metastasize (spread) to lymph nodes and other distant organs.

This cancerous growth has a propensity for growing within the trigone region of the bladder, the anatomical area where urinary tract plumbing is most complicated. It is here that the urethra and ureters connect into the bladder. It’s no wonder that TCC commonly causes a dog to experience difficulty urinating and, sometimes, even complete urinary tract obstruction.

Causes of TCC

Genetic predisposition and environmental factors likely play a role in most Cases of TCC. The genetic basis is strongly suspected because Scottish Terriers have as much as an 18-20 fold higher risk for this disease. Other predisposed breeds include, Shetland Sheepdogs, Beagles, West Highland White Terriers, and Wire Hair Fox Terriers.

Environmental factors that have been incriminated as risk factors for TCC are application of older generation pesticides and insecticides to the animal and exposure to lawn herbicides and pesticides. A study comparing 83 Scottish Terriers with TCC and 83 similarly aged, normal Scotties discovered that the group with cancer had greater exposure to lawns and gardens treated with insecticides and herbicides or herbicides alone. The effect of lawn and garden chemicals on other breeds has not yet been studied.

Smoking is the number one cause of TCC in people. It is not known if exposure to second hand smoke contributes to the occurrence of TCC in dogs.

Symptoms of TCC

The earliest symptoms caused by TCC vary from mild to severe, and often resemble those caused by a urinary tract infection. Such symptoms include:

  • Increased frequency of urination
  • Blood within the urine
  • Straining to urinate
  • Inability to urinate

Straining to have a bowel movement may be observed if the prostate gland becomes enlarged due to infiltration with TCC cells. When a dog becomes completely unable to urinate due to obstruction, systemic symptoms such as lethargy, vomiting, and loss of appetite will arise within 24 hours.

Diagnosis of TCC

TCC is suspected when a mass within the bladder is detected by an imaging study such as abdominal ultrasound. Growth of TCC within the urethra is best detected via endoscopy (a fiberoptic telescope device that allows visualization within the urinary tract).

Collection of tissue samples from the mass that are then processed and examined under the microscope is the only way to make a definitive diagnosis of TCC. Such tissue samples can be collected via surgery or endoscopy, and sometimes by urinary tract catheterization.

Other testing

Many dogs with TCC have a concurrent urinary tract infection, and a urine culture is performed to determine if antibiotic therapy is warranted.

Once TCC has been diagnosed, “staging tests” may be performed. Staging is the process used to determine if the tumor has spread to other sites in the body. Staging is warranted when the additional information these tests provide are important for providing ongoing care. The results of staging tests assist in:

  • Determining the prognosis.
  • Choosing the most appropriate course of treatment.
  • Establishing a baseline set of tumor measurements that will help determine if subsequent treatment is succesful.
  • Anticipating which future symptoms may arise.

Staging tests for dogs with TCC may include:

  • Blood and urine testing
  • Radiographs (x-rays) of the chest cavity to look for spread to the lungs and/or lymph nodes
  • Ultrasound of the abdomen to assess changes in the kidneys caused by possible obstruction to urine flow and spread of cancer to abdominal organs and/or lymph nodes

Treatment options

There are several options for treating TCC in dogs. Complete remission (complete elimination) of this cancer is always desirable, but this outcome tends to be the exception rather than the rule. Partial remission (reduction in the overall size of the tumor) and simply arresting growth of the tumor over a prolonged period are far more likely outcomes that usually result in restoring and maintaining an excellent quality of life.

Surgery

For dogs with TCC that has not spread outside of the bladder, complete surgical removal of the mass is the ideal therapy. Unfortunately, even for a highly gifted surgeon, this outcome usually isn’t possible. This is because TCC has a predilection for growing within the trigone region (neck of the bladder) where aggressive surgery would disrupt the delicate urethral and ureteral plumbing located there. Surgical removal works well when the TCC growth is relatively small and is located well away from the trigone.

Medical therapies

The medical options described below tend to be extremely well tolerated by most dogs. These drugs may be used individually, but it is not unusual for them to be used in combination to treat dogs with TCC.

Piroxicam

Piroxicam is an oral non-steroidal anti-inflammatory medication that substantially reduces the size of many TCC tumors. Piroxicam and other nonsteroidal anti-inflammatory medications (e.g., Rimadyl, Deramaxx, Previcox) are referred to as cyclooxygenase (cox) inhibitors. It so happens that TCC cells often produce and use cyclooxygenase, and inhibition of this enzyme can hinder tumor growth.

Piroxicam’s ability to influence the growth of cancer cells was discovered spuriously when the drug was being used to provide pain relief for dogs with cancer. Unexpected cancer remissions were observed. This resulted in a study of 34 dogs with TCC who were treated with piroxicam. The results were as follows:

  • Complete remission (cancer fully gone): 2 dogs
  • Partial remission (cancer reduced in size): 4 dogs
  • Stable disease (no change in cancer size): 18 dogs
  • Cancer increased in size: 10 dogs
  • Average survival time: 181 days

Mitoxantrone

A chemotherapy drug called mitoxantrone has also been used to succesfully treat TCC. A study of 48 dogs treated with the combination of piroxicam and mitaxantrone was performed by the Veterinary Cooperative Oncology Group. Results included:

  • Complete remission: 1 dog
  • Partial remission: 16 dogs
  • Stable disease: 22 dogs
  • Cancer increased in size: 9 dogs
  • Average survival time from start of therapy: 250-300 days

Vinblastine

A third drug for the treatment of TCC is vinblastine. This drug is typically used following failure of the other drugs mentioned above. A study using vinblastine to treat 28 dogs with TCC resulted in:

  • Partial remission: 10 dogs
  • Stable disease: 14 dogs
  • Cancer increased in size: 4 dogs
  • Average survival time from first vinblastine treatment: 147 days
  • Average survival time from the time of diagnosis: 299 days

Metronomic therapy

Metronomic chemotherapy refers to long term, low dose, frequent oral administration of a Chemotherapy drug. Metronomic therapy is given with hopes of blocking the formation of new blood vessels within the tumor, thereby inhibiting its growth. This is referred to as an “anti-angiogenic” effect.

A study of metronomic therapy for TCC was performed using a drug called chlorambucil (Leukeran). Of the 31 dogs studied, 29 had failed prior TCC treatment. The results are as follows:

  • Partial remission: 1 dog
  • Stable disease: 20 dogs
  • Progressive disease: 9 dogs
  • Lost to followup: 1 dog
  • Average survival time from start of therapy: 221 days

Radiation therapy

Radiation therapy is an option for control of TCC growth. Unfortunately, applied in suitable dosages, radiation therapy often produces harmful complications affecting the bladder and surrounding organs.

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CANINE HEMANGIOSARCOMA – THE ROAD FROM DESPAIR TO HOPE

Jaime F. Modiano, VMD, PhD, Michelle G. Ritt, DVM, DACVIM, Matthew Breen, PhD, CBiol, MIBiol, and Tessa Breen, BSc (Hons), Dip GD, CMM University of Minnesota, St. Paul, MN (JFM & MGR), and North Carolina State University (MB, TB)

In following article, we describe the current state of knowledge for canine hemangiosarcoma, including what it is, why it may happen, and how it can be managed. In addition, we present recent findings from our programs that promise to help us improve our ability to diagnose, treat, and prevent this disease.

knoop1The Natural History of Canine Hemangiosarcoma Canine hemangiosarcoma is among the most challenging and mysterious diseases encountered in veterinary practice. It is an incurable tumor of cells that line blood vessels, called vascular endothelial cells. Hemangiosarcoma is relatively common in dogs; it is estimated that this type of cancer accounts for 5-7% of all tumors seen in dogs. Considering the lifetime risk of cancer for dogs is between 1 in 2 and 1 in 3, we can calculate that 1.5 to 2.5 million of the ~72 million pet dogs in the United States today will get hemangiosarcoma and succumb from it. Although dogs of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly in dogs beyond middle age (older than 6 years), and in breeds such as Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Bernese Mountain Dogs, Flat Coated Retrievers, Boxers and Skye Terriers, among others. According to the Golden Retriever Health Study published in 2000, the estimated lifetime risk of hemangiosarcoma in this breed is 1 in 5, illustrating the magnitude of this problem.

knoop1Unlike other cancers, hemangiosarcoma is almost an exclusive disease of dogs. In people, a similar type of tumor (angiosarcoma) occurs only rarely in association with workplace exposure to vinyl chloride and polychlorinated biphenyls (PCBs), such as is found in rubber and tire plants. An even smaller fraction of women who receive high dose radiation therapy for cancer (usually breast cancer) can develop angiosarcoma of the skin. Yet, angiosarcomas account for much less than 1% of all tumors seen in people. Certain mutations are known to predispose laboratory mice to hemangiosarcoma, but whether these mutations contribute to the disease in dogs is not known. Benign tumors of vascular endothelial cells, called hemangiomas, arise in the skin of people and dogs that have extended exposure to sunlight. These tumors are distinct from hemangiosarcomas and angiosarcomas, and they are not life threatening.

knoop1In dogs, the common primary sites for hemangiosarcoma are the spleen, the right atrium of the heart, and the subcutis, which is the tissue beneath the skin. The pattern of growth for these tumors involves infiltration into normal tissues surrounding the tumor as well as distant spread (metastasis). The disease is indolent; in other words, it does not cause pain and the rate of growth in the early stages is relatively slow. Dogs harboring even large hemangiosarcomas may show no clinical signs or evidence that they have a life threatening disease. Generally, the tumor cells retain some normal aspects of behavior, so they try to make blood vessels. But these vessels are tortuous and malformed, and blood cells tend to pool in them and clot. The clots then prevent blood and nutrients from reaching tumor cells, in turn causing them to die. This creates small ruptures in the tumor through which blood may escape into the abdomen, heart sac, chest, or subcutaneous space. Depending on the amount of blood lost, affected dogs may show non-specific (constitutional) signs such as lethargy and weakness, but these are transient and resolve as dogs reabsorb the blood components and make new blood cells. The clinical signs are recurrent, but they also are subtle enough to go unnoticed for some time. Since hemangiosarcoma tends to metastasize aggressively to lungs, liver, intestines, and mesentery (the membranous connective tissue that supports the intestines), distant spread (either microscopic or macroscopic) has inevitably occurred once the disease is finally diagnosed. The eventual outcome for patients with this disease often follows the rupture of a large or rapidly growing tumor, which results in acute, severe hemorrhage, collapse, shock, and death.

knoop1What Causes Hemangiosarcoma. We do not precisely know what causes canine hemangiosarcoma. The observations that the disease occurs more commonly in dogs than in other animals, and that some breeds are at higher risk than others tell us that heritable factors must contribute to risk. Ultimately, the interactions of these heritable risk factors with the environment probably lead to the spectrum of mutations that give rise to the tumor. As a matter of brief review, it is important to understand that “cancer is a genetic disease, although it is not always heritable.” Tumors arise when cells accumulate mutations that eliminate normal constraints of growth and genetic integrity. These mutations provide cells a selective growth advantage within their environment, essentially the same evolutionary phenomenon that we call natural selection, albeit on a microscopic scale. Most mutations arise because the enzymes that control cell division are not foolproof. About 1 mutation occurs for each one to ten million bases that are replicated when time a cell divides (genomic DNA in dogs consists of about 2.5 billion base pairs; in other words, when a cell divides, it must copy 2.5 billion bases and the inherent error rate of the DNA replication machinery will introduce between ~250 and 2,500 errors, or mutations, to the DNA of each daughter cell). Since some cells in the body divide continuously to replace others that die or are damaged (for example, blood cells, skin cells, and gut cells), mutations are pretty much introduced constantly into cells in the body. For this reason, we say the greatest risk factor for cancer is “being alive”. As mentioned above in the example of humans that are at risk to develop angiosarcoma, mutations also can occur from exposure to environmental toxicants. Fortunately, most of these mutations are silent (they neither help nor hurt the cell or the organism), and the body has mechanisms to eliminate most cells that acquire deleterious mutations. A relatively new concept about how cancer happens invokes the theory that only “stem cells” can give rise to tumors, making the acquisition of mutations in somatic cells (any cell that is not a sperm or an egg) a lesser concern. This will be discussed in detail later in the article. For now, it is important to understand that simply carrying a mutation does not necessarily mean an individual will get cancer – it only means that his or her risk is elevated. The practical implication of this statement is that we will probably never eliminate cancer completely from our population (human or canine), but we can achieve a significant reduction in the number of cases as we learn more about how the disease happens and we work to diminish risk factors or detect the disease early enough to treat it before it becomes a life-threatening condition.

knoop1The news is not all bad. We have identified some of the fundamental properties of canine hemangiosarcoma, and it is possible one or more of these may prove to be an “Achilles heel” for the tumor. For example, most of these tumors make growth factors that they need to survive, or they “coerce” cells in their environment to do this for them. One of these growth factors is vascular endothelial growth factor-A or VEGF, which acts by binding specific receptors on the hemangiosarcoma cells. New drugs under development by various pharmaceutical companies are designed specifically to interfere with the signals transmitted by these receptors. The reliance of hemangiosarcoma cells on VEGF signals to survive should make them more sensitive than normal cells to these drugs. Several groups are working to bring these drugs into the clinic, but the process is slow because testing must be done in a careful, deliberate way to ensure the compounds are safe and effective. The rules for participation in clinical trials are stringent, but if you have a dog that is diagnosed with terminal hemangiosarcoma, your veterinarian may have information about trials for which he or she may be eligible. As we will detail below, our work and that of others continues to illuminate new avenues that we may be able to use to more effectively prevent, control, and treat this disease.

knoop1Treatment for Canine Hemangiosarcoma Regrettably, the standard-of-care for this disease has not seen significant advancement over the past 20 or 30 years. There is presently no readily available, effective test for early diagnosis of hemangiosarcoma. Careful analysis of blood samples by experienced pathologists may hint at the presence of chronic hemorrhage and blood vessel abnormalities that are suggestive of hemangiosarcoma. However, this method is neither sensitive nor specific to confirm the diagnosis. Non-invasive imaging methods are useful aids to diagnose the disease. In particular, ultrasound is moderately specific, but it is not sensitive, and the tumor must be large enough to be grossly visible. In addition, biopsies are required for confirmation of imaging results. Repeated biopsies of tissues where the tumors may arise (without other evidence for the presence of a tumor) are of little use to provide early diagnosis, and considering the fact that there is some risk to these procedures, such an approach is practically and ethically unacceptable.

knoop1The options for therapy of canine hemangiosarcoma are limited, largely because the disease is not diagnosed until the late stages. The standard consists of surgery to shrink or remove the primary tumor, when possible, followed by intensive chemotherapy. In some cases, surgery is not feasible, or it can be impractical or inappropriate (for example, if there is evidence of extensive metastatic spread to sites beyond the primary tumor). Median survival for dogs treated with surgery alone is approximately 90 days, and that is extended to approximately 180 days by the addition of chemotherapy using one of several protocols available. Because the goal for chemotherapy in pet dogs is to extend life with good quality, toxicity is generally not a major issue of concern, and when it occurs it is most often managed without much difficulty.

knoop1There is no other therapy that has been proven to be effective to manage or control hemangiosarcoma. As we will mention below, the cells that give rise to this disease originate in the bone marrow. We do not yet know when (or why) they localize to the organ where the disease will arise, but this means that prophylactic splenectomy (removing the spleen to prevent the development of the disease) is unlikely to have any benefit, since in the absence of a spleen, the transformed cell (or cells) can simply go to another organ. Also, the spleen is not simply a “window dressing” organ, and even though dogs can function without a spleen, they will have reduced ability to adapt or respond to a variety of conditions.

knoop1Several alternative and complementary approaches (diet, herbs, mystical energy, etc.) have recently become popular as people try to find treatments for canine hemangiosarcoma. This usually follows extensive publicity (such as from Internet chat groups) after a dog receives these treatments and survives longer than anticipated, leading proponents to advertise this as success and evidence that their approach is curative for hemangiosarcoma. The danger of attributing curative power to treatment approaches after an anecdotal response cannot be overstated. There is no reported case where one of these therapies has been consistently successful (or even as good as the standard of care) after it has been tested without bias to try to replicate the anecdotal response. In fact, sometimes such treatments can actually interfere with – or increase the toxicity of chemotherapy drugs. We know that when some tumors are caught early enough, surgery alone, surgery plus chemotherapy, and in some cases no treatment at all can lead to extended survival. In rare instances, the behavior of the tumor itself is such that disease progression is extremely slow and dogs can survive for an extended period regardless of the therapy used. This means that a small proportion of dogs diagnosed with hemangiosarcoma will live 2, 3, 4 years and longer even without aggressive management. Therefore, it is essential for families who have dogs that are diagnosed with cancer to recognize two things. One is that veterinarians would not willingly hold back effective therapies for any disease. Our job and our responsibility are to improve the health and well being of dogs and their families, and all of us would welcome an effective and non-toxic cure for this disease. The other is that there is no shortage of predators on the Internet and elsewhere who benefit from the desperation people feel when they know a beloved family member will probably die from a serious, incurable disease (please visit http://www.quackwatch.org/00AboutQuackwatch/altseek.html if you want to read more about “miracle cures” for cancer advertised in the lay press and on the Internet).

knoop1Hope for the Future. The unwavering support of the dog-loving community has already made a difference in our understanding of canine hemangiosarcoma. To end this article, we will highlight new information that makes us optimistic about our chances to win the battle against this disease. Here, we wish to note our gratitude for the support that our group and our collaborators have collectively received from dog clubs and owners alike, both financial and by making samples available for ongoing studies.

knoop1Development of a Test for Early Detection. As we mentioned above, one way to improve our success treating hemangiosarcoma is by detecting the disease early. Previous work from our group showed there are unique patterns of protein expression that can help distinguish hemangiosarcoma cells from normal blood vessel lining cells, even within the tumor. We also knew that most tumors shed some cells into the circulation. We reasoned, then, that we could take advantage of this to develop a test to look for tumor cells in the circulation, providing a minimally invasive, accurate diagnostic test for hemangiosarcoma. In many ways, this is similar to the proverbial search for a needle in a haystack. The tumor cells are so infrequent that they cannot be detected in routine blood tests, nor are they easy to enrich. To accomplish our goal, we needed to use a robust technology called flow cytometry. For this, cells are “tagged” with fluorescent molecules that identify their lineage of origin and then cells are run through an instrument (the flow cytometer) that combines sophisticated optics, fluidics and software that make it capable of analyzing tens of thousands or hundreds of thousands of cells in a matter of minutes. With financial support from the Portuguese Water Dog Foundation, Inc., the Portuguese Water Dog Club of America, and Idexx Laboratories, we were able to show proof of principle for this test. The work was published in the July 2006 issue of the journal Experimental Hematology. Idexx Laboratories has licensed the technology from the University of Colorado. As of the writing of this article, the test is in the final stages of optimization and transfer to Idexx for final testing. Several questions remain to be answered before the test can be offered commercially, not the least of which are cost analysis and market research to ensure that the final product is not only diagnostically useful, but also affordable for veterinarians and pet owners.

knoop1A planned future use for this test is its application to detect the presence of hemangiosarcoma in dogs at risk before the tumor poses a clinical hazard. As is true for other tumors, early detection is likely to offer the highest probability of successful treatment outcomes. There is, however, an important caveat. The presence of hemangiosarcoma cells in the circulation does not tell us where in the body the tumor is likely to develop, as tumors in the spleen, liver, heart, and skin all produce positive results in this test. Therefore, we have initiated several studies with support from the AKC Canine Health Foundation, the National Canine Cancer Foundation, and others, to develop novel treatment strategies for hemangiosarcoma that are independent of the site of origin (these are still in the earliest stages of laboratory development). Only then will we be able to ethically and judiciously use early detection to improve outcomes for dogs affected with this disease.

knoop1Is Hemangiosarcoma a Disease of Stem Cells? A lot of attention has been focused recently on stem cells and their potential use to cure a wide variety of diseases. The “dark side” of stem cells is that these may be the only cells that can give rise to tumors. It is very important to note here that this is not a reason to avoid or abandon research on the therapeutic promise of stem cells, as there is no practical, documented evidence that the possibility to develop cancer is any higher in laboratory animals or patients that receive stem cell transplants.
Until recently, the dominant theory for the origin of cancer assumed that all cells possess an equal capacity for self-renewal; that is, the capacity to make a new identical cell that retains all the properties of the mother cell, and that proliferation of cancer cells was a random process driven entirely by selection of mutations that increased the fitness of a cell in a particular environment. A competing theory now exists whose main concept is that self-renewal is limited to a small population of “cancer stem cells.” These cells possess the two features that define “stemness”: (1) self-renewal and (2) multipotency (the capacity to make new cells that can differentiate into more than one type or lineage). In other words, a very small number of self-renewing cells in a tumor generate large numbers of progeny that make up the bulk of the tumor (or tumors). The existence of “cancer stem cells” is now well documented; they have unique properties of gene and protein expression, and the initial transformation seems to involve a relatively small number of mutations. The accumulation of additional mutations determines the extent to which the progeny from these cells will differentiate, variably resulting in distinct clinical entities such as high-grade, aggressive tumors and low-grade, indolent tumors.

knoop1This model of cancer explains why multicellular animals like a dog, with trillions of cells in their bodies, can survive to reproductive age without developing cancer, as the capacity for tumor formation is limited to perhaps a few hundred “stem cells”, dramatically reducing the probability that any cell with cancer-causing potential will accumulate the set of mutations needed to develop the disease. Still, the high incidence of cancer among older individuals reinforces the notion that even with a limited number of susceptible stem cells, the probability to develop cancer over a long life is quite high. With regard to canine hemangiosarcoma, recent data from our lab support the idea that this is a disease of stem cells, the first such evidence for a canine tumor. Current work is focused on characterizing these stem cells, as their unique properties may provide opportunities to develop highly targeted, non-toxic therapies to effectively treat this disease.

knoop1What Are the Breed-Specific Risk Factors for Canine Hemangiosarcoma? We mentioned previously that hemangiosarcoma is a rather common cancer in certain breeds, including Golden Retrievers, German Shepherd Dogs, and Portuguese Water Dogs. This tells us that heritability contributes to risk, and so it may be possible to reduce the incidence by eliminating the highest risk alleles from the population. Moreover, if risk factors responsible for the disease are unique among breeds, we might have to consider the possibility that various new therapy approaches will have to be developed to effectively treat this disease in different breeds of dogs. To date, we have taken several approaches to identify how heritable factors influence hemangiosarcoma risk. One approach, developed largely in collaboration with Dr. Elaine Ostrander at the National Human Genome Research Institute of the National Institutes of Health and Dr. Kerstin Lindblad- Toh at the Broad Institute of MIT and Harvard, seeks to map risk alleles in Portuguese Water Dogs, Golden Retrievers, and German Shepherds using resources made available by the recent completion of the Canine Genome Project. We continue to collect samples for these projects, and we would be extremely grateful to owners who wished to participate by contributing blood and pedigree information from healthy (aged) dogs and from affected dogs. Information for participation is available at http://www.modianolab.org/studyInfo/studyInfo_index.shtml. A second approach, developed largely in collaboration with Dr. Matthew Breen, seeks to determine breed specific abnormalities that are detectable in tumors obtained from dogs of different breeds. We have made significant progress on this project, and have new data showing that, indeed, tumors from dogs of one specific breed are functionally and genetically more similar to each other than they are to tumors from dogs of other breeds. We are extremely excited about this information, as it will, for the first time, provide tangible evidence that heritable risk factors are a contributor to the development of canine cancer. More importantly, these results are the first step in our long-term goal to develop strategies for prevention and treatment that address specific causes underlying the biology of canine hemangiosarcoma.

knoop1In conclusion, hemangiosarcoma remains a devastating, untreatable disease of dogs. However, ongoing work in our laboratories and elsewhere is rapidly increasing our understanding of this disease, providing hope that we will achieve our goals to reduce its incidence and control its impact on dogs and their human families within our lifetime.

New therapy targets cancer in dogs.

Many of the 180 million cats and dogs in the  United States have moved from the wilds of the backyard to the warm and comfortable living quarters of their human owners. While this cushier existence is extending their lives, it also brings with it a higher risk of cancer and other diseases, according to Dr. Steven St. Peter, president and chief executive officer  of Aratana Therapeutics.

“Unfortunately, cancer is a consequence of living longer,” he said.

“Snoopy may have slept on top of his dog house, but now most dogs and cats are sleeping in the same bed with their owners and last year, $370 million was spent on pet Halloween costumes. I call this the humanization of pets,” St. Peter said.

Since pets are now viewed as family members and not property, their illness is seen as a family emergency, he added, and when a pet becomes ill, owners are more likely to seek treatment rather than euthanasia as the first course of action.

St. Peter said he established Aratana in 2010 to meet the needs of pets and give owners more choices for  their medical treatment.

Immunotherapies

One New Jersey business answering the call for more sophisticated treatments for cancer in pets is Advaxis, based in Princeton.

In March, the company which has developed Advaxis ADXS-cHER2 for the treatment of osteosarcoma (bone cancer) in dogs and three additional treatments for cancer, entered into a licensing agreement with Aratana Therapeutics, based in Kansas City, Mo.

Aratana will have exclusive rights to develop and commercialize the licensed immunotherapies for pet applications.

ADXS-cHER2 is an immunotherapy for the treatment of breast, gastric, esophageal and other cancers in humans and for osteosarcoma in canines, according to Daniel J. O’Connor, president and chief executive officer, Advaxis.

Considered to be the most common bone cancer in dogs, canine osteosarcoma is diagnosed in 8,000 to 10,000 dogs annually. Predominantly affecting middle to older-aged dogs and larger breeds, the cancer initially presents as lameness and, oftentimes, visible swelling on the leg.

Upon diagnosis, the standard treatment is amputation, followed by chemotherapy and in some cases radiation. Generally, the cancer cells spread to the lungs and lead to the animal’s  death.

O’Connor said  ADXS-cHER2 has demonstrated encouraging survival data in a  trial in canine osteosarcoma. These data provide the rationale to advance this same immunotherapy into a  clinical trial in women with HER2-positive breast cancer.

Under the agreement with Aratana Therapeutics, Aratana will focus initially on developing ADXS-cHER2 for osteosarcoma in dogs.

ADXS-cHER2 was validated in an ongoing clinical study in 13 dogs with osteosarcoma, conducted by Dr. Nicola Mason at the University of Pennsylvania, School of Veterinary Medicine and sponsored by Advaxis, O’Connor said.

He said in the study, dogs treated with ADXS-cHER2 immunotherapy after the standard of care (amputation and follow up chemotherapy) had a statistically significant prolonged overall survival benefit  compared with dogs that received standard  care without ADXS-cHER2,

The median survival time for dogs that did not receive ADXS-cHER2 immunotherapy was eight months, while the median survival time for those dogs treated with ADXS-cHER2 has not yet been reached.

The first three dogs treated with ADXS-cHER2 are alive, with each dog surviving over 21 months. As of March 21, a fourth dog named Sasha, passed away at 13.

Sasha underwent her first round of treatment on July 10, 2012. As of Jan. 23 this year, Sasha showed no disease progression.

According to O’Connor, the majority of treated dogs are tumor-free. There were no short or long-term complications associated with the immunotherapy and only low-grade, transient toxicities were reported in the study.

New tricks

What is exciting about the work of Advaxis from St. Peter’s perspective is that the company is drawing from cutting-edge science and applying  that to animal therapies.

“We are very encouraged by the results Advaxis has generated for ADXS-cHER2 in osteosarcoma, as well as the overall potential of their platform. Immuno-oncology is one of the most exciting advances in treating human cancers,” St. Peter said.

Advaxis immunotherapies utilize live, attenuated bacteria that are bioengineered to secrete antigen/adjuvant fusion protein designed to redirect the powerful immune response all human beings have to the bacterium to the cancer itself.

O’Connor explained that often, the body’s reaction to a tumor is to treat it as part of the body — therefore the body simply allows it to grow and doesn’t fight it.

“The ADXS-HER2 therapy has been developed using an engineered bacteria that essentially tricks the immune system into thinking that the tumor is a bacteria, which it will then attack,” O’Connor said.

He said some of our best medicines come from nature and the ADXS-cHER2 therapy is a powerful way of enticing the body to use its own resources to attack the cancer.

Both O’Connor and St. Peter are looking forward to continued success with ADXS-cHER2 and offering dog lovers as much time with their four-legged family members as possible.

According to St. Peter, the therapy could be available within 12 months.

For more information about the work of the two companies, visit www.advaxis.com and www.aratana.com.

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Pet Dogs Help Test Cancer Vaccine

By Susan Chaney
A dozen or so dogs will be part of the first test of whether a vaccine may eventually be used to treat osteosarcoma, a cancer which ultimately kills almost all dogs treated for it.

Right now, six dogs with osteosarcoma have been vaccinated at the University of Pennsylvania’s School of Veterinary Medicine. All dogs have undergone limb amputation to remove the primary tumor and follow-up chemotherapy prior to receiving the vaccine. Another four dogs will likely be vaccinated this month, and lead researcher Nicola Mason, B.V.M., Ph.D., and her team are already screening dogs for the next phase.

Five-year-old Bulldog Erma is part of a trial to determine whether a cancer vaccine is safe. Nicola Mason, B.V.M., of the University of Pennsylvania’s School of Veterinary Medicine is leading the trial. Photos courtesy of University of Pennsylvania.

Five-year-old Bulldog Erma is part of a trial to determine whether a cancer vaccine is safe. Nicola Mason, B.V.M., of the University of Pennsylvania’s School of Veterinary Medicine is leading the trial. Photos courtesy of University of Pennsylvania.

The vaccine consists of a genetically modified form of the bacteria listeria. It is modified to be much less virulent and to carry a tumor protein, Her2/neu. Phase 1 of the trial is testing the safety of the listeria vaccine which prompts a dog’s immune system to attack both the bacteria and the tumor protein it carries, thus generating an immune response against cancer cells. “The immune cells are geared to attack listeria, but they will also be trained to recognize and attack cancer cells that express the Her2/neu protein,” Mason says. “This protein is one of the few markers that distinguish cancer cells from healthy ones, so the stimulated immune system should attack the cancer.

“The vaccine aims to train the body’s immune system to attack cells that express the Her2/neu protein. We know that 90 to 95 percent of dogs with OSA have cancer cells somewhere else in their body at the time of diagnosis because despite limb amputation and follow-up chemotherapy they still die of their disease. The vaccine aims to stimulate an immune response that will target and kill these remaining tumor cells and so prevent recurrence of the tumor.”

About 50 percent of dogs with osteosarcoma express the Her2/neu protein in their tumor, Mason says. “Human tumors that express Her2/neu tend to be more aggressive than those that do not express Her2/neu. Patients with these Her2/neu positive tumors tend to have poor prognoses,” she explains. “Our preliminary data suggest that the same is true in dogs, that is, dogs with Her/2-expressing OSA tend to have more aggressive disease.” This has not been confirmed yet, but the suggestion of that possibility, she says, comes from data that’s been published and the data her team is collecting during the trial.

Sasha was the first dog to be vaccinated with modified listeria, designed to educate the dog’s immune system to attack the listeria as well as cancer cells.

Sasha was the first dog to be vaccinated with modified listeria, designed to educate the dog’s immune system to attack the listeria as well as cancer cells.

Although Phase 1 is about primarily about safety, the team is also looking at its therapeutic benefit. Two dogs in the trial have lived beyond the one year that most dogs survive after osteosarcoma treatment. One dog died before the first year passed. “The other three dogs are still alive and tumor-free, but haven’t quite made it to a year yet,” she says.

“Probably by the end of the summer we’ll have a good feel for whether we’re making a difference in the long term survival of these dogs.”

The team has seen very few side effects. “So far, it’s been very safe, both in acute and long-term follow-up,” Mason says. “At the doses we’ve tried thus far, it’s safe. That’s really what we’re interested in currently and that is very important.”

One missing piece of information is the median survival of dogs that express the Her2/neu protein. It may be that the dogs in the study would have died before that one-year mark without the listeria vaccine, or perhaps they would have lived longer than a year even without it.

A collaborator of Mason’s, Yvonne Paterson, Ph.D., a professor of microbiology at the University of Pennsylvania, has worked with modified listeria for much of her career. She knew it was a very strong stimulator of the immune system and recognized its potential to stimulate anti-tumor immune responses. “The idea is to genetically modify the bacteria so that it carries a little bit of tumor with it – the Her2/neu molecule. Then, when it is introduced into the body it will stimulate an immune response against cells that express Her2/neu. We are using the listeria as a Trojan horse,” Mason says.

Phase 2 of the trial will evaluate the effectiveness of the vaccine. “People who have dogs with osteosarcoma and are interested in participating in the clinical trial are welcome to contact me” through the university website, she says.

The listeria vaccination strategy, which is also being evaluated in women with cervical cancer, is being used by Advaxis, and Mason indicates that the Phase 2 clinical trial with the vaccine will be funded. “We’re interested in developing an effective vaccine for dogs,” Mason says. “Advaxis has a strong interest in making the vaccine available for veterinarians to use. However, if we find that this vaccine is effective in dogs with spontaneous tumors, then the chances are it will also work in humans.

“I really feel that we can help the dogs, and, as a bonus, we may be able to help humans as well. That just makes a lot sense.”

Mason is also looking for funding to evaluate the effects of the vaccine on dogs that have not had a leg amputated. These would be dogs that may have severe arthritis, problems with their cruciate ligaments or are just too big to move around well without a front leg. “We are interested in combining the vaccine with palliative radiation.” The study would determine whether an immune response along with radiation could kill the tumor. “We have the protocol set,” Mason says. “We’re waiting for institutional approval and looking for funding.”

The assistant professor of pathobiology and clinical studies is clearly upbeat by the promise that listeria holds. “It’s very exciting,” she says.

All of the dogs in Phase 1 have been examined, tested and vaccinated at the University of Pennsylvania. Nonetheless, the six enrolled dogs are from Ohio, North Carolina, Massachusetts, Delaware, New Jersey and Pennsylvania. The dogs are scheduled to be vaccinated next are from Illinois and Florida. The dogs needed to be close enough to travel to Philadelphia for checkups and in the case of some negative side effect. For Phase 2, Mason says it’s likely a couple of other academic centers will be involved. If so, dogs in those areas will also be able to participate.

Dogs in Phase 1 receive three listeria vaccinations three weeks apart, after which the dogs remain in the veterinary teaching hospital for 24 to 48 hours to monitor for any adverse reactions. In the next phase, dogs will also receive a single booster vaccine every two to three months to maintain immunity against the tumor. This vaccination schedule will be continued until such time as the disease progresses.

“Right now, things are starting to look quite promising,” Mason says.

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