Melanoma Research Advances With the Help of Canines
Dogs have been shown to develop the same types of cancer as humans. They are also exposed to the same carcinogenic environmental elements that humans are, which makes them highly translatable to humans and valuable participants in cancer research.P. Jack Hoopes, DVM, PhD
At a cancer center that treats humans, a translational research study has been showing great progress in treating oral melanoma in dogs from the local community. Dr. P. Jack Hoopes, DVM, PhD, and his research team are underway in a clinical trial to test a novel combination of therapies that effectively targets malignant melanoma cells.
Beginning with standard mouse models, Hoopes used a 2010 National Cancer Institute (NCI) grant to Dartmouth’s Geisel School of Medicine and Thayer School of Engineering to study the use of nanotechnology to treat cancer. The study looked at magnetic nanoparticle hyperthermia, which involved injecting non-toxic iron oxide nanoparticles into cancerous tumors and applying a non-toxic magnetic field, similar to an MRI field, to excite the nanoparticles. As a result, the tumor cells are killed by heat generated from intracellular nanoparticles (hyperthermia). The research also discovered that nanoparticle heat is capable of stimulating the body’s own cancer-targeting immune system to kill the cancer cells.
Combining treatment modalities
Building on the success of magnetic nanoparticle hyperthermia, and using his education and training in veterinarian pathology and radiation biology, Dr. Hoopes and his team next questioned whether this or other nanotechnology-based immunotherapy concepts could enhance more conventional cancer therapies, such as radiation. Hoopes and Radiation Oncology colleagues Drs. David Gladstone, ScD and Alan Hartford, MD, PhD tested this concept using an emerging type of radiation therapy that uses fewer but larger radiation doses. This technique, known as hypofractionated radiation, has the potential to be very effective with fewer patient visits.
Although the team had shown that hypofractionated radiation has excellent direct cell-killing benefits and had initiated improved anti-cancer immune response, the addition of more advanced immune stimulation techniques seemed desirable. Hoopes contacted his long-standing Cancer Immunology colleague, Dr. Steve Fiering, PhD. Dr. Fiering was working with a non-infectious plant virus that appeared, in mouse studies, to generate a meaningful anti-cancer immune response. Following successful mouse studies, Hoopes, Fiering, Gladstone and Hartford decided to test a combination of these treatments in the canine cancer setting. The initial study using two dogs focused on how hypofractionationated radiation can be effectively combined with low doses of magnetic nanoparticle hyperthermia and plant virus immunotherapies to enhance tumor response.
Recruiting canine patients
In order to further their understanding in a model that more closely resembles human cancer, Hoopes reached out to the local veterinary community, explained the focus of the research study and recruited two canine patients who had already presented with naturally occurring cancers and were being considered for standard treatment regimens. “Dogs have been shown to develop the same types and have the same cancer incidences as humans. They are also exposed to the same carcinogenic environmental elements that humans are, such as second-hand smoke and pesticides, which makes them highly translatable to humans and valuable participants in cancer research” explains Hoopes. Recognizing this fact, the NCI has initiated a permanent Comparative Oncology branch designed to facilitate the translational benefit of studying companion animal cancer genetics and therapeutic response.
The first canine cancer patient Dr. Hoopes’ team treated five years ago was Jenny, a then 10-year-old Schnauzer referred to the study by her veterinarian. Her oral tumor was successfully treated with radiation and magnetic nanoparticle hyperthermia. Interestingly, Jenny later developed an unrelated secondary carcinoma on a toe pad. Because this tumor had invaded the foot pad, the only known successful treatment was amputation of her entire front leg. Dr. Hoopes’ team instead treated it with a combination of hypofractionated radiation, magnetic nanoparticle hyperthermia and immunogenic plant virus nanoparticles. As of recent, the tumor was in complete remission and her foot functional when she died last month of age-related events. Jenny was 17 years old.
Phase II: Meet Clancey
Jenny’s treatment success opened up the second phase of Dr. Hoopes’ study late last year, which was to test all three therapies in combination. The first dog in phase II is Clancey (see main photo), a 10-year-old Rottweiler owned by Cyndi Scott, Assistant Director of Gift Planning for Dartmouth-Hitchcock Medical Center and Geisel. “Clancey had her head in my lap on the couch one night as she so often does and I noticed an unusual bump in her cheek that didn’t look like a tooth. I pulled her lip back and there was a tumor attached to the inside of her cheek and gum. I had an immediate sinking feeling,” says Scott. Clancey was diagnosed by her local vet and an oncologist in Williston, VT as having an aggressive malignant melanoma that was undetectable even a few short months earlier during Clancey’s regular wellness visit. The standard three-pronged treatment recommendation was surgery to remove the tumor and part of her mandible (lower jaw), followed by daily radiation available in Boston or Montreal as the closest facilities, followed by a melanoma vaccine that has limited effectiveness. “We were looking at upwards of $30,000” says Scott. “Considering the expense, the commitment of traveling, the time off work and putting Clancey through all of that, we were at a loss for what to do.” In the midst of these difficult decisions, through a former colleague and other DHMC connections, Scott learned of Dr. Hoopes’ research study. “I was interested in talking to him, but hesitant to get too excited that it was even an option for us” she explains. After speaking at length about the study with Hoopes and Karen Moodie, DVM, MS, who works in the Hoopes research laboratory, and learning that Clancey was eligible, Scott decided to enroll her.
At the end of 2015 as part of the study, Clancey received six radiation treatments to the local tumor site, two treatments of nanoparticle heating and two injections of the immunogenic viral-like particle into the tumor. Twelve days after the treatment, she developed a swollen lymph node in her neck on the same side as the tumor. Because the oral melanoma tumor almost always metastasizes (spreads) to this lymph node, the team feared the worst and removed the lymph node surgically. Much to Hoopes’ surprise and relief, upon further studying Clancey’s tumor under a microscope, he discovered the mass was not cancer at all, but rather a concentrated collection of immune cells. “The enlarged lymph node was produced as a result of the combined radiation and injected nanoparticle therapies, which we believe stimulated Clancey’s immune system to kill off residual cancerous cells,” Hoopes explains. It has now been 14 months since Clancey’s treatment and there has is no sign of oral melanoma recurrence. “It’s almost too good to be true,” adds Scott. “She has a good appetite, her spirits are up and she’s as playful as ever. Jack and Karen are helping manage some side effects of the high dose of radiation Clancey received because her cancer was so aggressive. They taught me how to check Clancey’s lymph nodes, so I’m doing that every day.” Still cautiously hopeful, Scott is reassured by Hoopes’ and Moodie’s genuine commitment. “They’ve assured me several times that they will be with her to the end. They won’t give up.”
Translation to human trials
Clancey’s and Jenny’s positive responses to the combination therapies they received suggests that the same success in human trials may be possible. Dr. Hoopes and his team have since responded to a Request For Proposal for an NCI grant that looks at DNA sequences in both canine and human cancers to determine if any of the mutated genes in the sequences are the same. All applicants for this grant must be associated with an NCI-designated cancer center, such as Norris Cotton Cancer Center. To make a grant like this work, the Dartmouth team will have to develop a close collaboration with community veterinarians and a local veterinary referral center. Hoopes’ team will collect the required 25 pathologically similar melanoma tumors for the purposes of biopsy, sequencing and comparison to both human melanoma cells and healthy tissue. Hoopes believes studies like this will lead to many more interesting and meaningful cases to treat as the Cancer Center’s newest canine patients.
Looking ahead, Hoopes’ study of magnetic nanoparticle enhancement of radiation and immune therapy for malignant melanoma, and hopeful receipt of the NCI grant under review looks promising in the field of translational research. While beloved family dogs have the opportunity to receive sophisticated and novel cancer treatment that is not normally available, the NCCC canine cancer studies may offer the ability to define successful new cancer therapies for humans—a bigger picture that Scott well remembers. “With every step of Clancey’s treatment, Jack and Karen show me what they’ve learned. Even though she’s receiving this great treatment, I wasn’t always sure I made the right decision. But in those moments of uncertainty, I’m reminded that we’re learning so much from her.”