A MUTUAL EXCHANGE
Ohio State researchers are integrating
studies of anticancer drugs for canines into
the development of drugs for humans for
the benefit of both
BY BOB HECKER
Hundreds of cancer patients are benefiting today from a novel drug called ganetespib that has roots in canine research at Ohio State.
Cheryl London, DVM, PhD, a canine cancer researcher in Ohio State's College of Veterinary Medicine and in the University's Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), led a phase I clinical trial evaluating ganetespib in dogs brought to the clinic with spontaneous cancer.
Ganetespib (or STA-9090) is a potent inhibitor of heat shock protein 90, a molecule that promotes the maturation and stabilization of several proteins important to cancer development.
London's studies show that ganetespib is effective in treating a variety of canine cancers, including mast cell tumors, osteosarcomas and thyroid carcinoma. "Given that canine and human cancers share many similarities with respect to tumor biology and heat shock protein 90 activation, it's likely that ganetespib will demonstrate comparable anticancer activity in human patients," she says.
At the 102nd annual meeting of the American Association for Cancer Research in April 2011, Synta Pharmaceuticals Corp., which developed ganetespib, reported on human clinical trials that demonstrated the drug's strong activity in both preclinical models and patients, particularly as a single agent in patients with drug resistant non-small-cell lung cancer (NSCLC).
Synta Chief Medical Officer Vojo Vukovic, MD, PhD, credited the work of London and colleagues for bringing ganetespib into the clinic.
"The results from our collaborators at Ohio State have been instrumental in helping us think through clinical trial choices for ganetespib on dose, schedule and biomarker evaluation," he said. "The single-agent activity seen in dogs with cancer has been encouraging and consistent with single-agent activity seen in human clinical trials."
Ganetespib is now being evaluated in more than 20 human clinical trials nationwide for patients with various cancers. At Ohio State, Gregory Otterson, MD, a researcher with the OSUCCC – James, is principal investigator for a pending study that will be part of an ongoing Synta phase II trial of ganetespib in a subset of NSCLC patients who are positive for the anaplastic lymphoma kinase (ALK) fusion gene.
Approximately 80 million dogs live in the United States, and about 1 million of them develop cancer each year. Many of these cancers are similar to their human counterparts in terms of the genetic changes that drive the malignancies.
With that in mind, researchers at the OSUCCC – James are increasingly collaborating with colleagues in Veterinary Medicine to integrate studies of anticancer drugsfor canines into the development path of anticancer drugs for humans, for the benefit of both.
The National Cancer Institute (NCI) calls this integration of research on naturally occurring cancers in animals with the study of cancer biology and treatment in humans "comparative oncology." Ohio State – which is an NCI-designated Comprehensive Cancer Center and has a freestanding cancer hospital, an Experimental Therapeutics Program, and colleges of Medicine, of Veterinary Medicine and of Pharmacy – can support a strong program in this innovative area of oncology.
This integration will likely enhance translational outcomes for both species, says London, who is a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program. "Evidence suggests that data from clinical trials in dogs with spontaneous cancer can be used to identify disease-related genes and to explore the safety and bioactivity of new therapeutic approaches to human cancers," she explains.
Why are canine and human cancer studies so similar? It starts with physiology. London says humans have a much closer anatomic relationship with dogs than with rodents, the most commonly used animal models for cancer research. Humans and dogs also have similar genetic alterations in cancer, similar therapeutic targets, and similar angiogenic and natural cell death (apoptotic) pathways.
"One of the challenging aspects of human cancer therapy is translating data from animal models to people," London says. "There are big metabolic differences between mice and humans. Mouse models have been good for working out the biology of disease, but they pose a challenge in assessing treatment efficacy and side effects.
"Dogs represent an intermediate step in translating data from mouse models. If a therapeutic agent has biologic activity in dogs, chances are you'll see it in humans too."
Michael Grever, MD, who chairs the Department of Internal Medicine and co-leads the Experimental Therapeutics Program at the OSUCCC – James, agrees.
"Canines enable us to test new therapies in a model that is much more relevant to human cancers than xenograft studies, which usually involve injecting a cancer cell line into the subcutaneous flank of a rodent," Grever says. "Xenograft studies provide information of tumor response in an in vivo model, but they do not reflect the natural history of a spontaneous tumor as in a dog model. And large animals offer a more robust model for evaluating drug tolerance or toxicity."
Canine trials also face less stringent FDA oversight than human trials and can thus be completed more quickly and with less expense.
"While clinical trials in client-owned dogs are conducted with care and caution, the FDA has fewer restrictions for these studies compared with early trials in human cancer patients," Grever says. "Changes in doses, schedules and combinations are faster and more efficient in canine patients, and this information facilitates future human trials."
"From a drug-development standpoint, canine studies generally are more flexible and move faster than human trials," says Timothy Wright, director of Ohio State's emerging Drug Development Institute. "These advantages offer a more efficient way of collecting needed information about a drug's behavior and toxicity while hastening our ability to move novel therapies into human trials."
London says the average timeline for human drug development is 10 years. "A clinical trial in children with bone cancer can take five years to accrue enough patients, and then another five years for outcomes," she says. "So 10 years pass before you know something new, which is why the field moves so slowly.
"But in veterinary oncology, we can complete a study in dogs with bone cancer within one year and have outcomes in two to three years."
She says the low rate of FDA approval for novel drugs as standards of care in human cancer stems from both the volume of regulations and guidelines and from the fact that many cancer drugs ultimately fail during later phases of testing.
"Cancer drugs often get to phase III studies and fail. At least 50 percent of the time, drugs that have shown anticancer activity in earlier phases don't work anymore," London says. "Why? Is it because we didn't get the dosing regimen right? Or that the mouse data simply didn't translate well?
"Mouse models that look promising often don't have the same level of therapeutic activity in larger animals. One of our goals with canine studies is to reduce the drug failure rate by providing enough reliable data for human studies to gain better results."
London says both humans and pets benefit from clinical trials in the veterinary setting. Pet owners who agree to enter their pets on a clinical trial gain access to advanced care at little or no cost, and critical information regarding the disease process and response to therapy is gained to advance the treatment of human disease.
"It's a win-win situation," she says. "And many owners feel good that their pets are in a clinical study that may also improve human health."
"From the human perspective," adds Lonnie King, DVM, MS, MPA, professor and dean of the College of Veterinary Medicine, "research involving novel agents in dogs with cancer can provide valuable information about side effects not identified earlier in the drug- development process, ways in which the drug can be given to enhance its activity, and biomarkers that can be used to predict which tumor is more likely to respond to therapy. From the veterinary perspective, our canine patients get cutting-edge treatments that can truly help treat their cancers."
Despite fewer FDA regulations, canine studies in companion animals at Ohio State adhere to Good Clinical Practice guidelines and are under close and collaborative institutional control. Ohio State is one of 20 academic comparative oncology centers involved in a Comparative Oncology Trials Consortium (COTC), which is centrally managed by the NCI's Center for Cancer Research Comparative Oncology Program.
And in 2007, the College of Veterinary Medicine formed its own Clinical Trials Office (CTO), which is directed by London and functions in much the same manner as the CTO at the OSUCCC – James, facilitating studies by taking on more of the administrative and regulatory burdens so researchers can concentrate on science.
"Guidance provided by our Veterinary Medicine CTO has helped our researchers more effectively interface with biotech and pharmaceutical companies, assisted in grant preparation when clinical projects are involved, and provided a mechanism for interfacing with other researchers at Ohio State and Nationwide Children's Hospital (NCH in Columbus, Ohio)," King says.
Veterinary Medicine researchers have been working with Ohio State's medical community and NCH on several projects, King says, adding that the most advanced involves the application of a novel STAT3 protein inhibitor developed by Jiayuh Lin, PhD, at NCH, and Chenglong Li, PhD, of the College of Pharmacy, to canine bone cancer (see "Campus Connections"). Lin and Li are also members of the OSUCCC – James Experimental Therapeutics Program. King notes that this work "represents a combined effort among several researchers across multiple colleges and at NCH."
"We do 25 to 30 clinical trials per year, and 60 to 70 percent of them are cancer-related," London says, noting that she and some other researchers in Veterinary Medicine are also members of the OSUCCC – James. "Our college can assist researchers at Ohio State and NCH by facilitating the drug-development process and by compressing the timeline for transition into human clinical trials, particularly for drugs developed at OSU."
A plan is in the works, she adds, for the College of Veterinary Medicine CTO and Biospecimen Repository (CTO/BR) to become a Shared Resource with the OSUCCC – James. Jeff Walker, senior executive director for the OSUCCC – James, says the plan is far enough along for the CTO/BR to be considered a "developing" Shared Resource.
Patrick Green, PhD, professor and associate dean of Veterinary Medicine and leader of the Viral Oncology Program at the OSUCCC – James, believes this Shared Resource "will fully integrate the comparative and translational medicine efforts of the CTO/BR with those of Ohio State's Medical Center, Comprehensive Cancer Center and Nationwide Children's Hospital. This is likely to result in improved translational outcomes in both human and veterinary medicine through early evaluation of novel therapeutic approaches that can help guide the future use of such therapies to treat human and animal disease."
Wright says the College of Veterinary Medicine "has created a sound strategic and financial business plan to execute successfully in comparative oncology. Ohio State is positioned to lead this on a national basis, and the OSUCCC – James is supporting this effort directly. Both our Comprehensive Cancer Center and Drug Development Institute are bullish on the promise of collaborative studies with Veterinary Medicine."
"The Veterinary Medicine resource adds to the enormous potential at Ohio State for drug development," Grever says. "Having multiple interactive bioscience medical colleges on one campus will place us at the forefront of therapeutic advancement."
CHERYL LONDON, DVM, PhD,
Assocaite Professor of Veterinary Medicine and holder of the Thekla R. and Donald B. Shackelford Professorship in Canine Medicine
London appreciates the support and believes it is justified. Besides the ganetespib studies, she can cite examples of other canine trials that have benefited human cancer research:
• OSUCCC – James researchers led by John C. Byrd, MD, are finding in a phase II human clinical trial that an agent called PCI-32765, also known as ibrutinib, is highly active and welltolerated in patients with chronic lymphocytic leukemia (CLL) who were previously untreated or who have relapsed and are resistant to other therapy. This inhibitor is the first to target Bruton's tyrosine kinase (Btk), a molecule required for activating the B-cell receptor signaling pathway, which contributes to CLL and other B-cell malignancies. London notes that the initiation of Byrd's trial was supported by an earlier study that evaluated this agent in dogs with spontaneous B-cell non-Hodgkin's lymphoma. That study showed that ibrutinib effectively inhibited Btk in canine lymphoma patients and that this was associated with clinical responses, providing early support for the subsequent human clinical trials in B-cell malignancies.
• London led part of a national research effort to evaluate toceranib, a tyrosine kinase inhibitor that blocks several receptor tyrosine kinases involved in tumorigenesis and angiogenesis (VEGFR, PDGFR, Kit, Flt3). Biologic activity in dogs with several types of cancer (carcinomas, sarcomas, melanoma) was demonstrated, supporting the development of a similar drug, sunitinib, for humans with cancer. In 2009, toceranib became the first drug approved by the FDA specifically to treat cancer in dogs.
• London and colleagues are evaluating KPT-335, an inhibitor of the protein CRM1 that controls the shuttling of many key proteins in and out of the cell nucleus. Disrupting of CRM1 function results in failure of normal nuclear transport and death of tumor cells, making it a prime therapeutic target. London says work with KTP compounds in dogs in lymphoma, mast cell tumors, osteosarcoma and melanoma is guiding the development path of a similar drug, KPT-330, in humans.
Still other canine trials, including some with the COTC, are ongoing or pending at Ohio State. London projects even more will arise as the University's drug-development efforts escalate. "
It's phenomenally rewarding to contribute not only to veterinary medicine but to the human side as well; to see a new agent that has a beneficial effect on patients is what keeps me motivated," she says. "I hope referring physicians and their patients find it equally exciting that cancer studies involving pets can also help people.
"We're all in this together, and there's no reason that we can't all learn from everything we do."
To learn if a pet could benefit from a
College of Veterinary Medicine clinical
trial, please contact the Clinical Trials
Office at 614-688-5713 or via email at