In the Greek tale of the Trojan horse, soldiers hid inside a large wooden horse, which was then placed outside the walls of Troy. Thinking it a gift, the citizens wheeled the horse inside the city. Once inside, the soldiers sneaked out and overtook the city. Think of that same strategy in terms of battling cancer. What if something could hide until it has made its way deep inside a tumor, then suddenly become active and kill off all the cancer cells from the inside out? This Trojan horse anecdote is one that cancer research scientist Joseph Bauer, Ph.D. uses to illustrate how his approach to chemotherapy works.
While in graduate school and reading a biochemistry book about vitamin B-12, it hit him. Why not get the vitamin to secretly carry a deadly chemotherapy agent into the tumor? Dr. Bauer’s invention uses B-12 to deliver the anticancer drug, nitric oxide, to the tumor. Cancer cells love B-12, actually having receptors to draw it into the tumor. They are completely fooled because they have no idea that a deadly agent lurks inside. “The nitric oxide that’s released inside the tumor cell has a half-life outside the cell on the order of milliseconds. It doesn’t have time to kill the surrounding cells, so it just kills the tumor cell,” Dr. Bauer explains. “Then, with the cancer cells dead and the nitric oxide no longer active, the vitamin B-12 can get out into the blood stream and help the body heal.”
Dr. Bauer’s “biological Trojan Horse” may be one of the best things to happen in cancer research in recent years. Preliminary National Cancer Institute testing noted its anti-cancer effects, showing inhibition of the growth of human tumor cells on 60 different types of cancer. This vitamin B-12 based compound, nitrosylcobalamin (NO-Cbl), preferentially targets cancer cells with minimal side effects to normal cells. Learn more here.
Tales of the ‘Trojan horse drug’ and the ‘miracle dogs’
American Chemical Society Press Release
SALT LAKE CITY, March 23, 2009 — Diagnosed with an extremely aggressive form of cancer called anal sac adenocarcinoma, Oscar’s future seemed bleak. Bedridden and unresponsive to chemotherapy or radiation, he would be lucky to survive three months. But thanks to an innovative new drug treatment, Oscar’s cancer receded and he was walking again within two weeks.
Oscar’s recovery was extraordinary enough, but his case was unusual for another reason. Oscar is a Bichon Frise, who scientists reporting here today at the 237th National Meeting of the American Chemical Society call “the Miracle Dog.” Joseph A. Bauer, Ph.D., and colleagues described promising results with a drug called nitrosylcobalamin (NO-Cbl) in battling cancer in Oscar and three other canines without any negative side effects. While it gives profound hope to dog owners, NO-Cbl also points to a powerful new cancer treatment for humans — one that infiltrates cancer cells like a biological Trojan horse.
“We are one of the few research groups that is offering to treat dogs with cancer that otherwise have no hope,” Bauer said. “With no other options available, most people in this situation opt to euthanize so that their pets don’t go through the pain of disease and trauma of surgery.”
About six million dogs are diagnosed with cancer each year in the United States. According to the National Cancer Institute (NCI), pets with cancer provide a win-win opportunity for cancer researchers. Scientists can study new cancer treatments in animals other than lab mice. And pets get access to new treatments that provide hope and in instances like NO-Cbl, additional time.
Bauer put it this way: “The beauty of using a dog or a cat to test a cancer drug is two-fold. First, the animal can get the benefit of the most up-to-date drug in cancer medicine. Second, the NCI gets data on pets that are exposed to the same environmental factors their owners are. They breathe the same polluted air and drink the same polluted water that you and I do every day. If you can find an agent to treat cancer that occurs in a dog with success, there is a higher likelihood that you can take that to the human population and have a much higher response rate than with mice.”
Although NO-Cbl has been used in only a few dogs, daily treatments have led to promising results in each case. “In all four dogs, there has been a significant reduction in tumor size without any toxic side effects or discomfort,” says Bauer.
Oscar was the first success story. Since then, Bauer has treated two other dogs. A six-year old golden retriever named Buddy was unable to walk due to a spinal tumor pinching essential nerves leading to his right hind leg. After nine months of daily NO-Cbl treatment, Buddy’s tumor shrank by 40 percent and he was going on two mile walks. A 13-year-old female Giant Schnauzer with inoperable thyroid carcinoma also showed tumor reductions of 77 percent in less than 10 weeks.
“Our case studies demonstrate anti-tumor efficacy with limited toxicity to normal tissues,” Bauer added. “NO-Cbl sensitizes multidrug-resistant cancer cells to the antitumor effects of several different drugs, so it may be valuable when utilized in combination regimes,” he added.
The drug targets cancer cells with “biological Trojan horse technology.” Cells have receptors for vitamin B12 on their outer surface. The receptors serve as docking ports where molecules of the vitamin, essential for cells to divide and multiply, attach and then enter the cell. In order to divide at their abnormally rapid pace, cancer cells grow extra B12 receptors — 100 times more than normal cancer cells. Scientists have been trying since the 1950s to exploit that vulnerability and make B12-based drugs that attach to the receptors, sneak into the cell, and deliver a knock-out dose of medication.
Bauer and his colleagues from the Cleveland Clinic attached nitric oxide (NO) molecules to vitamin B12. NO kills cancer cells. The B12 acts as the Trojan horse, easily slipping into cancer cells. The subsequent release of toxic NO kills the cancer cells from within.
The team’s goal is to successfully treat 10 dogs with NO-Cbl and slingshot the drug into human use as soon as possible. Because of the genetic similarity between dogs and humans, Bauer says his approach should have a much better chance of getting through the FDA’s strict drug approval chain.
But Bauer stresses he wants to get the NO-Cbl dog treatment approved, as well. “I’m committed to the animals, and my goal would be to do a dual clinical trial, Phase One human and Phase One dog,” says Bauer.
Oscar is still alive and well. Today, Bauer is treating another Golden Retriever named Haley with a spinal tumor.
“This is one of the most rewarding things I’ve ever done in my life,” says Bauer, the owner of a two-year old Beagle. “It gets boring working in the lab, but to see the fruits of your labor in a positive outcome like this and to know you’re responsible in some small way, that’s pretty cool.”
The Bauer Research Foundation was established to promote the drug discovery work of Joseph A. Bauer, Ph.D. Their mission is to promote and provide ethical and equitable therapies to fight cancer in animals.
Currently, the Bauer Research Foundation is working with local veterinarians as well as veterinary offices in Pennsylvania, North Carolina, Georgia, and Florida to treat dogs and cats with a vitamin B12-based chemotherapy agent, nitrosylcobalamin (a non-toxic drug, patented in 1999). Animals will be accrued (informed consent) through the offices of local veterinarians and animal hospitals. Eligibility requirements include 1) Animals must have a reasonable performance status (can walk and eat on their own), 2) No prior anti-tumor therapy is preferred but animals with a minimum of 6 weeks since last treatment may be considered, 3) Tumor size of 7 cm diameter or less is preferred, 4) Tissue biopsy is required to establish the diagnosis, 5) Eligibility decisions will be made on a case-by-case basis.
Once eligibility requirements are met baseline imaging (MRI preferred) will be performed. The animal’s veterinarian will demonstrate, to the owners, the technique for subcutaneous (under the skin) injection. This allows the owner to administer NO-Cbl to their dog on a daily basis in the comfort of their own home. Monthly blood draws will be taken at the veterinary office to ensure the health and safety of the patient and to monitor for any signs of toxicity. The blood draws will analyze basic blood chemistries including liver enzymes, GGT, and BUN, creatinine (to assess kidney function), serum nitrate, serum B12, and complete red blood cell and white blood cell count, including differential counts. If the drug is well-tolerated after three months, with the consent of the veterinarian, the blood draws can be limited to every other month. A follow-up MRI will be required every 6 months.
From Ken & Marti Johnson of Akron, OH, here is the story of Golden Retriever Buddy. He is definitely a wonderful success story as a result of receiving this cancer targeting therapy.
Buddy – Meet Dr. Bauer!
Buddy now enjoys his daily walks, almost limp-free, and constantly retrieves silly things, as only a Golden can. We would never have got to where we are, had it not been for Dr. Bauer’s care and persistence. His research means the world to us; we only hope expanded use of this therapy will lead to even greater results, and not just for the canine community.
A visit to the Pittsburgh clinic on Feb. 27, 2009 confirmed that the tumor has shrunk again, now having shrunk by 70% of what it was when the treatment began.
Buddy showed no ill effects from the drug; his activity and appetite were unaffected, and we slowly but surely noticed a change in his general demeanor. His limp got slightly less pronounced over the first few months, and his movement in general seemed more like the ‘old’ Buddy. He also seemed to be pain-free. As the months went by, these changes became even more pronounced. A follow-up MRI in August of 2008 brought some wonderful news: his tumor had shrunk by about 40%. Our enthusiasm was matched by Dr. Bauer’s: we continued with the drug regimen, which continues to this day.
When our normally bouncy Golden Retriever, Buddy, began balking every time I tried to take him for his daily walk back in the late spring of 2007, I thought it was time to call in the ‘dog whisperer’. What had been one of his favorite activities to that point became an effort in futility. He’d just stop a few steps into the walk, plop on his hind end, look up at me, as if to say, ‘It wouldn’t be prudent to continue, not at this juncture’.
At that time, he seemed to be showing no other signs of physical discomfort, but to be on the safe side, we took him to our family vet, hoping for a simple explanation of what might be going on. Nothing was evident, and when Buddy then began to develop a slight limp in his right front leg, our vet suggested some X-rays. These also proved negative, but then during a follow-up exam, a point of tenderness was found deep in Buddy’s shoulder. An MRI was suggested, and a trip to PetsDX in Pittsburgh ensued. The results were devastating to us: a large tumor was discovered, and Buddy was given little chance to survive beyond six months or so.
We brought him home, realizing by now the cause of his reluctance to walking all this time, and tried to keep his environment as comfortable and safe as possible. He showed few other effects of the tumor, other than the pronounced limp which by now had gotten significantly worse. His love for people, however, was unaffected, and that’s when fate intervened. One afternoon, a normal ‘potty’ break outside was interrupted when Buddy suddenly spotted a familiar face down the street, one of our neighbors enjoying a walk with her two dogs. He limped on down to say hello, as only he can, setting in motion a chain of events which has brought us to where we are now.
Naturally, a conversation ensued, and Buddy’s health became the primary topic. The neighbor, Kari Bauer, mentioned that her brother, Dr. Joe Bauer, was engaged in canine research specifically related to carcinomas, and might be able to help us.
From that point on, Buddy’s world, and our world, changed dramatically. After reviewing the X-rays and MRI results, Dr. Bauer concluded that Buddy would be a good candidate for his current research, and the drug therapy associated with it. We got Buddy started almost immediately, and with a little help from our vet, learned how to administer Buddy’s twice-daily injections prescribed by Dr. Bauer of nitrosylcobalamin (NO-Cbl) based on vitamin B12, in February of 2008.