A Twist of Fate

There are a few things you need to know about Raymond Reilly. The self-effacing associate professor of pharmacy doesn’t give up easily. And he’s not given to dramatic exaggerations. So when he says that his almost decade-long effort to bring his novel breast cancer therapy to the stage where it can be tested on humans was a challenge, you can assume it’s an understatement.

Another thing to know about Reilly is that he doesn’t turn up his nose at the gifts of serendipity. Consider this anecdote:

The University of Toronto professor, who is also a scientist with the Toronto General Research Institute, had been anxiously trying to find a source for a rare biological substance that he needed before his therapy could proceed to clinical trials. He had exhausted his options through traditional avenues. He was, he says, at wit’s end. So late one evening, as a last resort and expecting nothing, he turned to Google.

Reilly typed “pharmaceutical quality epidermal growth factor” into the search engine and, to his surprise, the query produced three hits. The last link, from a biotechnology company in Ithaca, in Upstate New York, turned out to have the stock, the quality of material and the desire to supply research efforts such as Reilly’s. Nine months later, Reilly’s unique targeted radiation therapy was being tested on breast cancer patients in Canada, the first in the world to receive the breakthrough treatment.

To know Raymond Reilly’s story is to understand a lot about the story of new cancer therapies: they almost never involve a smooth trajectory from stunning laboratory results to patient benefits. More often, the tale is an epic of wrong turns, aggravating switchbacks and the infrequent interventions of fate. Above all, the narrative is one of perseverance. But when researchers such as Reilly prevail, the world ends up with ever-more sophisticated, effective therapies to beat back mankind’s most flummoxing diseases. In other words, the endings of such tales can be very satisfying indeed.

Cathie Long (BA 1971 Trinity) is an accountant, a mother and an avid French horn player. But ask her to explain Reilly’s unique treatment, and she sounds a lot like a biophysicist. Long, 56, has a vested interest in understanding how and why Reilly’s approach has potential in the fight against breast cancer.

Long, who lives in Cobourg, Ontario, found out she had aggressive breast cancer in 1995. She underwent surgery, chemotherapy and radiation, then enjoyed nearly seven years of remission. But in 2002, she felt a pain near her sternum that turned out to be cancer; the disease had metastasized. Since then, she has tried radiation treatment and four separate chemotherapy regimens. She suffered from fatigue, hair loss, gastrointestinal effects and a blood disorder in the process.

The Canadian Cancer Society reports that nearly 150,000 people in Canada were diagnosed with cancer in 2005. Although lung cancer is still the leading cause of cancer deaths among adults, breast cancer continues to affect more Canadian women than any other form of the disease.

In the past 20 years, the understanding and treatment of cancer has been helped immeasurably by genomics. The sequencing of the human genome, completed in 2003, has enabled researchers to identify a host of genetic targets in cancer cells and develop new therapies. Recently, a related field called functional proteomics has energized cancer research. This specialty identifies the proteins produced by genes, and proteins are often the first warning sign of disease.

Long has a type of breast cancer that produces a particular protein. Those with breast cancer producing this protein tend to have a poorer prognosis than those with other forms of the disease. As it happens, Reilly’s novel therapy targets precisely the kind of breast cancer cells that are invading Long’s body. His treatment takes the old workhorse therapy of radiation and makes it more deadly, more effective and less toxic by getting it inside these individual cancer cells.

Long was asked to take part in the earliest human experiments with Reilly’s targeted approach, and she decided to opt in. “I had developed resistance to chemotherapy, and I wasn’t a candidate for [the cancer drug] Herceptin,” she says. “The approach of delivering radiation in a really targeted way made sense to me.”

Like so many researchers throughout the history of science, Reilly stumbled on a new way to treat cancer while looking for something else.

For much of his career, Reilly made radiopharmaceuticals. These compounds emit gamma rays that are captured by sophisticated cameras and produce images similar to a CT scan. They help radiologists “see” disease, infection or injury in the body. Different radiopharmaceuticals can help visualize different ailments. And early on, Reilly began thinking about designing radiopharmaceuticals that help doctors detect specific kinds of cancer.

His work in imaging and diagnosing disease led to his interest in designing a radioisotope that would not only locate breast cancer, but also tell doctors about the idiosyncrasies of each tumour. “Breast cancer is not just one disease, though often it is treated that way,” he says. “Tumours differ because of their biology. Some are more aggressive than others.”

Tumours, like cats, can be very finicky about what they eat. Reilly wanted to understand the specific growth factors, or proteins, preferred by the tumours of different breast cancer patients. The rationale was simple: the more information doctors can have about the specific diet of each tumour, the better they can use drugs and other therapies to interfere with the diet that allows the tumour to grow unchecked.

Cancer specialists were already well aware that certain breast cancers have a healthy appetite for the hormone estrogen. Inside these cancer cells are entities called estrogen receptors, which attract the hormone and absorb it directly into the cancer cell nucleus, where it triggers cell growth.

By the time Reilly began his doctorate work in medical biophysics in the mid-1990s, these estrogen-receptor-positive breast cancers were being successfully treated with drugs such as tamoxifen, which inhibits the cancer cell’s ability to take up estrogen and slows cell growth. But not all breast cancers are hungry for estrogen. Reilly became interested in another kind of tumour, which is harder to diagnose and treat. “I wanted to identify patients with a poor prognosis – those who don’t respond to tamoxifen and who might need to be treated more aggressively with chemotherapy,” he says.

By poring over research literature, Reilly found that breast cancers that don’t feed off estrogen have another kind of receptor – one that attracts a peptide called epidermal growth factor (EGF), which is produced by the body’s salivary glands.

Reilly speculated that if he attached a radionuclide to EGF, it would act like a homing device and take the imaging tracer directly to cancer cells with EGF receptors. The radionuclide would cause the EGF-receptor-positive tumour to light up on the camera image, creating an easy, accurate and non-invasive way to diagnose this more stubborn subset of cancer tumours.

So in 1996, Reilly was well on his way to developing a helpful new imaging agent. Little did he know that the fickle gods of research had something a little different in mind. In the midst of his doctoral work, Reilly attended a meeting of the Society of Nuclear Medicine where he noticed a research poster that only a radiopharmacist could love. It described how a decaying radiopharmaceutical (a form of iodine 125) could damage a cell’s DNA by emitting Auger electrons. Named for the French scientist Pierre Auger, who first published research on them in 1925, these electrons have a low energy and can only travel short distances – mere nanometres. But this is all that’s needed to wield a hefty blow within the confines of a cancer cell nucleus.

Reilly was dumbstruck by the enormity of the possibilities. He was using another Auger-electron emitting radioisotope called indium-111 for his work on a new imaging agent. It occurred to him that the tool he was developing to better diagnose EGF-receptor-positive breast cancer might actually end up treating it.

When scientists try to decode their complex drug delivery work to a lay­person, they often use metaphors of weaponry and stealth: the smart bomb versus the carpet bomb, or the sniper versus the indiscriminate machine gun. Way back in 1996, Reilly started to think of his potential new therapy as a Trojan Horse – a way of smuggling a deadly payload into enemy territory under the guise of something friendly. He had a good hunch that if he attached indium-111 to the EGF peptide (to create an EGF conjugate) it would be taken inside EGF-receptor-positive cancer cells. And he bet that when indium-111 started decaying in the cell, the emitted Auger electrons would be close enough to the cell nucleus to irrepara-bly damage its DNA. In other words, he planned to exploit the cancer cells’ appetite for EGF by feeding them what they wanted – and smuggling a radioactive ambush into each cell.

Back in the lab, Reilly found that radio-labelled EGF could actually kill breast cancer cells. In fact, when Reilly compared his indium-111 EGF conjugate to the conventional chemotherapy drug methotrexate, the conjugate was 300 times more toxic to cultured breast cancer cells. Never in his professional life had he come this close to yelling, Eureka! “I couldn’t believe it,” he says.

Last October, Long got her one-and-only intravenous treatment of indium-111 EGF as part of the Phase 1 clinical trial for the therapy. Her ears momentarily turned red. Her blood pressure dipped slightly. And, for a brief moment, she felt nauseous. Small stuff.

Long kept her sense of humour, especially about the precautionary measures. She wasn’t allowed to sleep next to her husband for the first week. She also had to flush the toilet three times after using it, keep her towels separate, stand back a few metres from anyone she encountered and avoid public transportation. Because indium-111 is a radionuclide, it’s regulated by the Canadian Nuclear Safety Commission – and that means lots of precautions.

“It was overkill really, but in terms of inconvenience it is minor compared to six months of chemotherapy,” says clinical scientist Dr. Katherine Vallis, a U of T associate professor of radiation oncology and medical biophysics.

Several years ago, Vallis, who is also a radiation oncologist at Princess Margaret Hospital, joined forces with Reilly to get his therapy ready for clinical trials. Together, they’ve spent much of the intervening years proving that indium-111 EGF is worthy and safe for testing on humans.

EGF receptors are not only produced by specific cancers, they occur on the surface of healthy cells in the liver and kidneys. The team had to show that the indium-111 EGF conjugate would not be unduly toxic to these organs or the bone marrow. Once they developed animal models to test their therapy, they were in for a happy surprise: even at 42 times the planned maximum dose for humans, the new therapy tested on mice resulted in no toxicity to the kidneys, liver or bone.

Despite these cheery results, the process of obtaining Health Canada approval for their clinical trial had as many ups and downs as a barometer in spring. (Pharmaceutical companies have whole departments dedicated to ensuring that promising drugs make it through the rigorous government approval process. Academic researchers, such as Reilly and Vallis, must deal with all of the paperwork themselves.) “Certainly there was a point where we thought the regulators were demanding so much that we did some heart-searching about what our role was – if, in fact, we should just do the preclinical work and leave the actual trials to someone else,” says Vallis.

In total, it took 18 months and 1,300 pages of documentation to gain Health Canada approval. In his office, Reilly devotes most of a long shelf to the fat white binders that house these documents.

“It was the worst-case scenario,” says Reilly. For starters, the team was testing a conjugate that had never been pre­viously studied in humans. Also, the conjugate was a radiopharmaceutical – one that emits radiation. Finally, the radioisotope was attached to EGF, a biotechnology product that itself attracts a high level of regulatory scrutiny.

In January, the Phase 1 clinical trial of indium-111 EGF was 18 months old and six months shy of completion. The team has gradually increased the dose levels throughout the trial in an attempt to determine the highest dose that can be safely administered. So far the Phase 1 trial has confirmed that indium-111 EGF is safe for human use.

This confirmation is fuelling a lot of plans. Reilly and Vallis are exploring new clinical-trial possibilities for other cancers that express EGF receptors. They’re also considering the potential of conjugating the breast cancer wonder drug Herceptin to indium-111. They hope the result would combine the super drug’s growth-inhibiting factors and the Auger electrons’ cancer-killing properties to deliver a one-two punch to cancer cells. And they are looking for an industrial partner to help them move their indium-111 EGF breast cancer therapy to the next level of clinical trials. If these trials are successful, and the team continues to receive funding, the novel treatment could be approved for use by the end of the decade.

Long received only one injection and at a low dosage. Since then, she has made the 80-minute trip between Cobourg and Toronto for hours of followup. And yet for someone with a lot at stake, she keeps a sublimely practical outlook.

“I feel justified in saying that whatever the outcome of this particular clinical trial, even if it doesn’t go the way I hope, things will be learned from it to use for the future,” she says. “My cancer is slow-growing though incurable and progressive. So there is a little time to experiment on me, and it’s my way of giving back to the people and the whole system.”

Certainly Long understands as well as the researchers that developing a new therapy can move as slowly and in as tiny increments as an Auger electron. But if the ultimate effect is precise and inexorable, she figures it will be worth the risk she decided to take. Reilly meanwhile, is keeping counsel with the type of optimism that researchers who’ve faced a mountain of challenges are best at – the guarded yet hopeful kind.

Krista Foss is a writer in Hamilton, Ontario. She wrote “Miracle at Sick Kids” in the Summer 2005 issue.