Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
Comparative Oncology Reveals Canine/Human Similarities, Points to New Treatments
Days after agreeing to address a two-day workshop on how clinical studies for pets with naturally occurring tumors can be integrated into developing drugs for human cancers, the topic hit home in the worst way for J. Leonard (Len) Lichtenfeld, M.D.
Dr. Lichtenfeld, deputy CMO for the national office of the American Cancer Society, learned that his 11-year-old golden retriever, Lily, developed swelling in her face. The next day, Dr. Lichtenfeld’s family veterinarian delivered the sad news: Lily had lymphoma. A week later, a mass found on her back leg turned out to be a sarcoma. Early last month, Lily died peacefully.
“This became, quite frankly, very personal,” Dr. Lichtenfeld told attendees June 9 at the workshop’s wrap-up session, the grief audible in his voice.
The next day, he shared the story on his blog. “Our family is still mourning the loss of our lovely Lily. She was so much a part of our lives with a docile demeanor that made her very special and very much loved,” Dr. Lichtenfeld wrote. “The question becomes for us and for so many who have had similar experiences: What can we do to honor those precious lives which gave us so much unconditional love? Is there an opportunity to make life better for our companions and at the same time inform the human condition?”
Answers to those questions will emerge, researchers hope, through comparative oncology, the branch of cancer research focused on studying naturally occurring cancer models in pets, then applying what is learned from them to human cancer R&D.
Acknowledging the progress and addressing the challenges of comparative oncology was the goal of the workshop, hosted by the Institute of Medicine’s National Cancer Policy Forum. Twenty-one researchers and other stakeholders led attendees in identifying two priorities for veterinary oncology research: more fully characterizing the genetic makeup of tumors in both dogs and people, and further investigating the role of cancer immunology in dogs.
Dogs appear to be ideal pets for such research, since strong similarities in the genetic aberrations and gene-expression patterns of dog and human cancers have been confirmed in the decade since the sequencing of the dog genome. Dogs develop cancer as they age, just like people. Because tumors develop spontaneously, the tumor population is heterogeneous, as it is in humans. The size of tumors is similar in both dogs and humans, as is the speed of tumor growth, notes Timothy M. Fan, D.V.M., Ph.D., associate professor of veterinary clinical medicine at University of Illinois at Urbana-Champaign.
In 2007, Dr. Fan and colleagues began studying the anticancer drug procaspase-activating compound-1 (PAC-1) in pet dogs with naturally occurring lymphomas and osteosarcomas. PAC-1 is a small molecule designed to activate procaspase-3 to caspase-3, resulting in apoptosis of cancer cells in patients with advanced malignancies.
PAC-1 was developed by another U-of-I professor, Paul J. Hergenrother, Ph.D., who collaborated with Dr. Fan on testing the drug in canine cancer patients. By itself, PAC-1 exhibits only a modest activity. It appears to be more effective in combination therapy. For example, it enhances the activities of cancer-fighting therapies such as radiation, monoclonal antibodies, and chemotherapy.
One canine patient, an eight-year-old Labrador retriever whose MRI was consistent with meningioma, showed positive results after being treated with a combination of oral PAC-1 and the chemotherapy drug temozolomide.
“We had an over 50% reduction in tumor volume with that combination, which is very unusual,” Dr. Fan told GEN. “We don’t typically see responses in that tumor with a conventional chemotherapeutic agent. When we combined it with PAC-1, we really had a pretty good response. But again, it’s very, very early data.”
It is also too soon, Dr. Fan added, to say whether PAC-1 will prove better at fighting brain cancers than cancers outside the brain, where the compound has also generated promising findings in preliminary studies. In pets with brain cancer, he said, the early positive responses with PAC-1 likely reflect both its ability to get into the brain—it penetrates the blood-brain barrier—and its ability to combine with other anti-brain cancer agents.
Given its favorable characteristic of penetrating into the brain, PAC-1 is now envisioned primarily as a way to treat cancers that affect the brain or central nervous system, Dr. Fan added.
PAC-1 is now the subject of a Phase I trial in humans being sponsored by U of I and a university-launched startup, Vanquish Oncology, which was formed to commercialize targeted cancer therapies. Dr. Hergenrother is a co-founder of Vanquish, for which Dr. Fan is a paid consultant and shareholder.
The trial’s initial study will evaluate PAC-1 in cancer patients without brain involvement. After the completion of that study, the second part of the trial will assess PAC-1 activity in combination with temozolomide for people with glioblastoma multiforme.
Dr. Fan and colleagues hope PAC-1 will prove effective against cancer in people and dogs. Only a handful of cancer drugs are available for canine patients:
- Palladia (toceranib phosphate), the first canine cancer treatment, is a tyrosine kinase inhibitor indicated for mast cell tumors. The drug won FDA approval in 2009 before its current manufacturer, Zoetis, was spun off from Pfizer.
- Kinavet CA-1 (masitinib mesylate), from AB Science, has conditional FDA approval for use against mast cell tumors.
- Paccal Vet-CA1 (paclitaxel for injection) has conditional FDA approval for use against mammary carcinoma and squamous cell carcinoma. It was developed by Oasmia Pharmaceutical, which recently regained exclusive global distribution rights from Zoetis. On July 7, Oasmia said that it had established a U.S. sales company to market the drug.
The U.S. Department of Agriculture (USDA) has fully licensed the canine melanoma vaccine Oncept, a xenogeneic DNA expressing the human tyrosinase gene and marketed by Sanofi’s Merial. The USDA has also conditionally licensed a pair of monoclonal antibody therapies marketed by Aratana Therapeutics—AT-005 for T-cell lymphoma, which targets CD-52, and AT-004 for B-cell lymphoma, which targets CD-20.
Developing Best Practices
As trials for new treatment candidates take shape, oncologists will need to agree on best scientific and ethical practices for conducting clinical trials for animal patients, Rodney Page, D.V.M., director of the Flint Animal Cancer Center at Colorado State University, stated at the workshop.
As with human trials, he said, clinical trials for animals should include peer review; accountability and oversight measures (such as open access to all primary data, including negative data); a trials registry; an informed consent process; a continuous education and improvement process; and best supportive care, including relief of pain and other distressing symptoms.
“[We have an opportunity to] take advantage of…the human regulations for clinical trial conduct that are already in existence,” Dr. Page told GEN. “We don't have to reinvent many of the wheels.”
According to Dr. Page, the workshop identified two key research priorities:
- Better characterize the genetics of cancers in companion animals. Doing so would be similar to creating The Cancer Genome Atlas,” Dr. Page said, referring to the effort aimed at applying genome analysis technologies, including large-scale genome sequencing, to better understand the molecular basis of human cancer. The Atlas is a joint effort of two NIH divisions, the National Cancer Institute (NCI) and the National Human Genome Research Institute.
- Further investigate the immune system in the dog. This line of inquiry requires the development of new tools that can reveal how the canine immune system responds to cancer and to certain products.
While investigational drugs have successfully fought cancer in mouse models, only about 1 of every 10 agents that show significant activity in mice will show similar activity in humans. Lab-induced cancers in mice differ greatly from the cancers of people and dogs. And some human cancers seldom occur in dogs, such as the diet-driven colon cancer. Yet researchers are often limited to comparisons with mice and humans, Dr. Page said, given the much bigger “toolbox” of available research.
Mice will continue to be used in cancer research: They are cheaper to raise, they have shorter lifespans, and they can produce specific and uniform genetic traits. PAC-1 is being studied in mice, Dr. Fan said, as well as in vitro in cell cultures combining low levels of the compound with small-molecule inhibitors.
Ultimately, fighting canine cancers and translating those insights to humans will require integrating clinical trials for pets into translational cancer research and development. Coordinating such trials is the work of the Comparative Oncology Trials Consortium (COTC), a network of 20 academic comparative oncology centers managed by the Comparative Oncology Program, a resource launched by the NCI’s Center for Cancer Research.
Another consortium valuable to studying canine cancer focuses on tissue and other samples from patients. The not-for-profit Canine Comparative Oncology & Genomics Consortium (CCOGC) operates the Pfizer-CCOGC Biospecimen Repository, which houses more than 60,000 samples across seven spontaneously arising cancers: osteosarcoma, lymphoma, melanoma, pulmonary tumors, mast cell tumor, soft tissue sarcomas, and hemangiosarcoma.