f e a t u r e Man’s Best Friend in More Ways Than One

Cancer drug development typically begins with in vitro research before proceeding through varying degrees of investigation in cell lines and laboratory animals, eventually culminating in human clinical trials. However, this often arduous development path may now find an ally in a relatively new branch of research, referred to as comparative oncology. Initiated and directed by Chand Khanna, D.V.M., Ph.D., the CCR Comparative Oncology Program complements translational research through the characterization of relevant and naturally occurring cancer models that develop in pet animals as a window to evaluate novel therapies.

It was nearly Christmas when Prince, an amiable, nine-year-old Labrador retriever was diagnosed with oral malignant . His owners, Frances and Peter Way, wanted the best treatment for their

(Photo: Frances and Peter Way) companion, so when veterinarians at Colorado State University’s (CSU) Animal Cancer Center suggested a clinical trial, the Ways readily agreed. Prince’s melanoma was very aggressive, similar in many ways to human melanoma, and the Animal Cancer Center was part of a consortium, sponsored by CCR’s Comparative Oncology Program (COP), through which are treated with experimental therapies to prepare for their use in human Prince. clinical trials. Prince was treated with

22 ccr connections | VOLUME 5, NO. 2 | 2011 f e a t u r e a new immunotherapy and achieved a robust response, living for almost “It became clear to me that there would be great a year. “That’s a lot longer than we think he would have otherwise,” value in including pet animals with cancer within said Peter Way, from Fort Collins, our CCR studies.” Colo. “We were hoping for a cure, but we also knew this would help the science, and I was glad that Prince while he was a postdoctoral fellow In 2004, with backing from could participate. It fit his spirit and in CCR, in the lab of Lee J. Helman, Helman and Carl Barrett, Ph.D., his attitude; he was a great .” M.D. At the time, he was working on then Chief of CCR’s Pediatric tumor and , Oncology Branch and CCR’s Director, Addressing a a bone cancer that occurs in pediatric respectively, Khanna established the Lost Opportunity patients and is also common in dogs. COP. Its mission, Khanna explained, To date, the COP has treated more “It became clear to me that there is to improve the assessment of novel than 150 dogs over the course of would be great value in including pet treatments for humans by treating nine clinical trials conducted by animals with cancer within our CCR pet animals—primarily dogs with its leadership of the Comparative studies,” Khanna said. “There are very naturally occurring cancers—while Oncology Trials Consortium (COTC), few human cancers that don’t also also trying to give these animals a collaborative network of 20 occur naturally in pet animals. To better quality of life by offering them veterinary schools from around the me, not learning from their cancers the benefit of cutting-edge research country overseen by Melissa Paoloni, to help inform human clinical trials and experimental therapies. “The D.V.M. Khanna conceived of the COP seemed like a lost opportunity.” ultimate goal was for NCI to engage Associates)

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The Comparative Oncology Trials Consortium (COTC) is an active network of 20 academic comparative oncology centers, centrally managed by CCR’s Comparative Oncology Program.

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research organizations involved in cancer drug development. The COP then chooses participating sites

(Photo: R. Baer) based on their availability, access to advanced technology (such as PET scans, for instance), and other factors. Once approved, researchers at chosen sites enroll dogs according to eligibility criteria that—mirroring the situation with human clinical trials— can be very strict. For instance, many studies exclude dogs with other co- morbidities, such as renal failure or cardiac disease. COP Trials Prince was enrolled in a study of two immunocytokine fusion proteins in tumor-bearing dogs, which aimed Chand Khanna, D.V.M., Ph.D. to define optimal doses and early indications of antitumor activity. the drug development community, “He’d get a monthly injection and then and to lead a consortium of ...human and canine periodic bloodwork,” said Susan Lana, veterinary schools in a program cancers are very D.V.M., Chief of Clinical Oncology at to supply clinical research results Colorado State University Veterinary that might accelerate new human similar with respect Teaching Hospital and Animal Cancer treatments, and simultaneously to their genetics and Center. “And we would follow the help pet animals with cancer,” tumor as he progressed. Prince was a Khanna said. biological features. good candidate because, although his tumor was large, he was healthy in all A Logical Partnership other respects.” According to Khanna, enrolling pet genome sequence in 2005, scientists The first of the COTC’s studies dogs in clinical trials has the potential can now understand the molecular was sponsored by CCR and conceived to offer some key insights into changes that are associated with a through a collaboration of CCR’s human drug research. Dogs routinely treatment response and a treatment Surgery Branch and COP, and develop osteosarcoma, lymphoma, failure. And finally, the COTC studies individuals at M.D. Anderson Cancer , head and neck cancer, spontaneously occurring tumors in Center in Houston, Tex. Led by Paoloni, malignant melanoma, and mammary pet dogs, which are far more similar to that study investigated the safety cancer. Moreover, human and canine human cancer than tumors induced and effectiveness of using a bacterial cancers are very similar with respect to artificially in mouse models of cancer. phage to deliver tumor necrosis their genetics and biological features. “It’s also important to note that the factor (TNF)—an inflammatory On a practical level, the compressed COTC provides cutting-edge cancer cytokine—directly into tumor blood life span of a dog and the more rapid treatment to pets whose owners might vessels by intravenous dosing. TNF- course of cancer progression makes not otherwise be able to help them,” alpha was already approved for it easier for scientists to evaluate the said Paoloni. “It can cost thousands local administration in melanoma benefit of novel cancer therapy in a of dollars to pay for cancer therapy and soft tissue , but with short period of time. Repeat biopsies in a dog, and unfortunately that puts systemic dosing, human patients ran are often easier to perform in dogs it out of reach for many families, so a high risk of hypotension and other than they are in people, making canine our efforts can help both human and cardiovascular reactions. The phage pre- and post-dosing tissue studies to veterinary cancer patients.” was designed to avoid that problem by investigate drug-target interactions According to Khanna, COTC targeting a molecular marker on tumor feasible. Additionally, thanks to projects emerge from collaborations blood vessels. Thus, the phage would the public release of the canine with the drug industry and other theoretically spare normal vasculature

24 ccr connections | VOLUME 5, NO. 2 | 2011 f e a t u r e and avoid cardiovascular and other toxicities. However, it was not practical to test the phage in healthy animals without cancer because animals (Photo: R. Baer) lacking the tumor marker would simply excrete the phage. During the trial, COTC scientists at five participating universities tested the phage in a pair of sequential studies. That data is now being used as a basis for the first Phase 1 clinical trial in humans, Paoloni said. According to Khanna, many COTC studies strive to predict appropriate human doses of new cancer drugs. “We want to know the relationship between dose and effect at a molecular level.” Furthermore, he said, “There is a great need to answer simple questions that Melissa Paoloni, D.V.M. would optimize the success of future human trials. This can be as simple as: When is the best time to conduct a biopsy after dosing to see if a drug did Many COTC studies strive to predict appropriate what it was intended to do?” In a pilot study that is nearing human doses of new cancer drugs. completion, the COTC is investigating the feasibility of collecting, processing, and analyzing tissues from multiple This pilot study, Paoloni said, the COTC’s role would be to oversee sites for molecular markers in precedes a trial planned for next and advise on trials run by the under a week, a clinically necessary year—also sponsored by TGEN—to pharmaceutical industry.” timeline. According to Paoloni, this determine if appropriate therapies The Way family’s opinion is that particular study, which is sponsored can be prescribed on the basis of Prince was an active partner in the by the Translational Genomics molecular profiling to support the COP’s research. “It wasn’t easy,” they Research Institute (TGEN), a non- clinical utility of individualized cancer said. “Although we worked with great profit organization in Phoenix, Ariz., care. Two additional trials planned for veterinarians in the program, it was will confirm COTC’s future ability to the coming year involve new areas of emotionally hard to go through it. participate in large-scale, molecular research for COTC investigators: one But we thought the program could research in personalized medicine. aims to determine if molecular results benefit a lot of people, and that was “It’s crucially important that we can obtained from tumor biopsies can important to us. We all have friends process tissues and generate accurate be predicted by advanced imaging or family who have struggled with or molecular readouts quickly,” Paoloni technologies, and a second is focused died of cancer and this was a positive said. “There are many examples of on discovering the novel mechanism thing for us and our dog to do.” failures that may occur with sample of action for a compound currently processing in the era of targeted cancer in the clinic. “These are both exciting To learn more about Drs. Khanna therapy. You cannot underestimate studies,” Paoloni said. and Paoloni’s research, please visit Dr. how important it is to be able to collect Asked about long term plans Khanna’s CCR Web site at http://ccr. samples correctly—otherwise the for COTC, Paoloni envisions the cancer.gov/staff/staff.asp?name=khanna. promise of personalized medicine will future this way, “Essentially, we be difficult to realize.” Lana agrees, want to demonstrate the utility of To learn more about the Comparative pointing out that in a “non-clinical this model so effectively that large Oncology Program, please visit the Web world” it might take months to generate pharmaceutical companies begin site at https://ccrod.cancer.gov/confluence/ that kind of information. “Patients with to develop their own comparative display/CCRCOPWeb/Home. cancer can’t wait that long,” she said. oncology programs. In that case,

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