In a new commentary appearing in the August 2nd issue of the journal Science, Carlo Maley and Darryl Shibata describe the dynamics of this sexually transmitted disease, which arose in a single ancient animal, living as much as 8.5 millennia ago.

Intriguingly, the exploration of long-term, multi-generational cancer evolution in CTVT may shed new light on how human cancers evolve during the typical course of the disease and may inspire new approaches to treating cancer, which remains the second leading cause of death worldwide.

“Cancers evolve, and our strategies for managing cancer need to take that into account,” Maley says. In the future, we hope to maintain long-term control over these evolving tumors. CTVT is fascinating because it shows us how cancers might evolve over the long term.”

Maley is a researcher in the Biodesign Center for Biocomputing, Security and Society, the Center for Immunotherapy, Vaccines and Virotherapy and the Center for Mechanisms of Evolution at Arizona State University, as well as ASU’s School of Life Sciences. He is the director of the newly established Arizona Cancer and Evolution Center (ACE). Shibata is a professor in the Department of Pathology at USC and the co-director of the ACE Center.

Ominous signs emerge

Examples of contagious cancers in humans exist, but they remain exceedingly rare and have never spread beyond a second host. Other animals however are less fortunate and may fall prey to a range of transmissible cancers, which vary in the severity of their impact.

In 1996, a mysterious illness began sweeping through animal populations in the central highlands of Tasmania. The island’s Tasmanian devils were dying from a gruesome facial tumor. At first, a virus was the suspected culprit in the rapidly spreading epidemic. But when the DNA fingerprints of afflicted devils were examined, researchers made a remarkable discovery. The tumor cells were genetically distinct from the devil’s own healthy cells, yet they matched tumor cells taken from other Tasmanian devils with the facial tumor disease. It was as though the tumor cells had been cloned and transplanted into each stricken animal. The disease was positively identified as an aggressively lethal, transmissible cancer.

The current commentary concerns CTVT, which causes grotesque, oozing tumors that afflict the genital area in dogs. When researchers sequenced cells from these tumors, the results mirrored those observed in the Tasmanian devils. All of the cancer cells shared a suite of genetic variants that did not appear in the dogs’ healthy cells. This led to a startling conclusion: CTVT is not simply a disease that occasionally develops in dogs. It arose only once, in a single dog and has been transmitted through the ages from one animal to the next ever since.

When two dogs with CTVT were examined, one in Brazil and another in Australia, each belonging to a different breed, their tumor cells shared nearly 2 million mutations that were not found in normal canine DNA. While the CTVT genome diverged considerably from the original dog genome, it remained remarkably stable over time.

Dog years

Unlike the pitiless cancer devastating the Tasmanian devils, CTVT is rarely lethal. Instead, it typically persists for a matter of months before being cleared by the dog’s immune system. (See drawing based on genetic sequencing of what the first dog carrying CTVT may have looked like.)

Recent investigations of CTVT, carried out by Adrien Baez-Ortega and colleagues, advance the unusual story of this disease. Their findings appear in the current issue of Science and are the focus of Maley and Shibata’s commentary.

Baez-Ortega, a researcher at the University of Cambridge, sequenced tumors from 546 dogs around the world. The results showed the great antiquity of CTVT, which has been transmitted by dogs for 4000 to 8500 years. For evolutionary biologists like Maley and Shibata, the findings are revelatory, in part because CTCV appears to have stopped evolving long before it spread around the world.

New directions

The study of cells derived from transmissible cancers like CTVT provides valuable clues for biologists interested in the development of human cancers. Examining somatic cell evolution around the world and over significant spans of time helps researchers understand the subtle dynamics of the evolutionary processes involved in cancer. (In contrast, observing the life and death of cells over time in an individual patient is very difficult.)

Perhaps the most critical observation resulting from the genome sequencing of CTVT is that cancer is not an inevitably progressive disease. Rather, tumors may reach an optimal state that can stabilize over time, exhibiting little or no additional gains in biological fitness — the ability to survive and reproduce.

Typically, tumors persevere and wreak havoc by generating numerous mutations. While most of these have no effect on cancer cell survival, or are even harmful, a few convey an adaptive advantage to cells, increasing their survivability. These are known as driver mutations and as the name implies, they are responsible for a successful cancer’s relentless expansion. Driver mutations generate the cells that are able to resist cancer treatment.

It appears that CTVT has been evolving neutrally after its inception, accumulating mutations that do not affect fitness. The successful development of CTVT in dogs therefore seems to require only a few minor adjustments to the genome. The lack of ongoing natural selection in CTVT also suggests that the disease has not had a significant impact on dog survival and reproduction.

The stability of CTVT over time offers hope that certain slow-growing human cancers resistant to conventional therapy, for example prostate cancer, could be tamed and controlled. This might be achieved through so-called adaptive therapies, which seek to limit tumor growth as opposed to aggressive treatments aimed at total eradication, which invariably select for resistant and often lethal cell variants. A pilot clinical trial to test this approach in metastatic breast cancer will soon start at the Mayo Clinic’s Arizona campus, in collaboration with ASU.

It seems likely that ongoing explorations of cell evolution in CTVT will provide further insights into complex cell trajectories and genetic transformations in a range of human cancers and inspire innovative methods of addressing the disease.

“Most cancers can only evolve for a few decades before they die with their host,” Maley says. “CTVT is an incredible natural experiment, which showed us that it doesn’t take much for a cancer to reach an optimal state. It is amazing that it did not discover additional adaptations over thousands of years, even as it infected all different breeds of dogs in all different environments around the world.”

The team was able to extract the compound from the flowers and modify it so it could be used to kill chronic lymphocytic leukaemia (CLL) cells in the laboratory.

Feverfew is grown in many UK gardens, and also commonly sold in health food shops as a remedy for migraine and other aches and pains.

The compound the Birmingham team were investigating is called parthenolide and was identified by scientists as having anti-cancer properties several years ago. Although available commercially, it is extremely expensive with poor “drug-like” properties and has not progressed beyond basic research.

The Birmingham team were able to show a method not only for producing the parthenolide directly from plants, but a way of modifying it to produce a number of compounds that killed cancer cells in in vitro experiments. The particular properties of these compounds make them much more promising as drugs that could be used in the clinic.

The parthenolide compound appears to work by increasing the levels of reactive oxygen species (ROS) in cells. Cancer cells already have higher levels of these unstable molecules and so the effect of the parthenolide is to increase levels of these to a critical point, causing the cell to die.

The study, published in MedChemComm, was a multidisciplinary programme, drawing together researchers from the University’s Institute of Cancer and Genomic Studies, the School of Chemistry and the drug discovery services companies, Sygnature Discovery and Apconix. The University of Birmingham’s Winterbourne Botanic Garden oversaw the cultivation of the plants in sufficient volume for the drug screen to take place.

It was initiated by Dr Angelo Agathanggelou, of the Institute of Cancer and Genomic Studies, who is investigating new ways to treat chronic lymphocytic leukaemia (CLL), a type of cancer which typically affects older people.

Dr Agathanggelou explains: “There are several effective treatments for CLL, but after a time the disease in some patients becomes resistant. We were interested in finding out more about the potential of parthenolide. With expertise from colleagues in the School of Chemistry we’ve been able to demonstrate that this compound shows real promise and could provide alternative treatment options for CLL patients.”

Professor John Fossey, of the University’s School of Chemistry, says: “This research is important not only because we have shown a way of producing parthenolide that could make it much more accessible to researchers, but also because we’ve been able to improve its “drug-like” properties to kill cancer cells. It’s a clear demonstration that parthenolide has the potential to progress from the flowerbed into the clinic.”

Lee Hale, Head of Winterbourne Botanic Garden and Abigail Gulliver, Winterbourne’s Horticultural Adviser oversaw the cultivation and harvesting of the plants.

Hale explains: “After trials on related plant species within the Asteraceae family it soon became apparent that Tanacetum parthenium — feverfew — provided the optimum levels of parthenolide.”

“Feverfew is a short lived perennial plant which we sowed on an annual basis for the trial to ensure continuity of supply. This was necessary as winter weather can result in plant losses,” adds Abigail Gulliver.

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Prion diseases occur when normally harmless prion protein molecules become abnormal and gather in clusters and filaments in the body, including the brain. The diseases are thought to be always fatal. Scrapie, which affects sheep and goats and can be adapted to rodents, is closely related to human prion diseases such as Creutzfeldt-Jakob disease, which is currently untreatable. Thus, scrapie is a valuable experimental model for the development of human prion disease therapies.

In the studies, National Institutes of Health scientists and their colleagues injected ASOs into the spinal fluid of mice already infected with scrapie or that were challenged with scrapie proteins within weeks of the injection. Ionis Pharmaceuticals specifically designed ASO1 and ASO2 to reduce the rodents’ supply of normal prion protein. Rodent studies using different dosages of ASO1 and ASO2 were conducted at Rocky Mountain Laboratories (RML) in Hamilton, Montana, (part of the NIH’s National Institute of Allergy and Infectious Diseases) and at the Broad Institute of Cambridge, Massachusetts.

RML scientists injected either ASO1 or ASO2 into mice 14 days prior to infecting them with scrapie, and then seven or 15 weeks after infection. Mice treated with ASO1 did not show clinical signs of disease for a median 250 days, or 82% longer than untreated mice (137 days), and they lived 81% longer than untreated mice (259 days versus 143 days). Mice treated with ASO2 did not show clinical signs of disease for a median 272 days, or 99% longer than untreated mice (137 days), and they lived 98% longer than untreated mice (283 days versus 143 days). In the Broad Institute experiments, mice received either ASO1 or ASO2 2 weeks before infection with scrapie and then seven weeks after infection. Both ASOs delayed rodent weight loss. Mice treated with ASO1 and ASO2 both lived longer than untreated mice, by 61% (274 days versus 170 days) and 76% (300 days versus 170 days), respectively.

The RML group also tested the ASOs against established prion disease, treating mice 17 weeks after they were infected with scrapie — near the onset of clinical signs. Mice treated with ASO1 did not show signs of clinical disease for a median 189 days, or 33% longer than untreated mice (142 days). They also showed slower disease progression and lived 55% longer than untreated mice (244 days versus 157 days). ASO2 had no beneficial effect.

The researchers plan to expand their scrapie ASO studies to human prion diseases. Other researchers have seen promising initial results in humans with ASOs directed against Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and Huntington’s disease.

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