Solving the cancer puzzle

Cancer is one of medicine’s biggest puzzles. A major reason? Researchers have been missing a key piece – a map of the human genome. With that now in hand, the bigger picture is finally taking shape. Dr Douglas Schwartzentruber recently tested a vaccine for metastatic melanoma, with promising results.

Dr Bryan Schneider seems much younger than his 37 years. Part of the reason, I suspect, stems from his boyish eagerness to share his research with me. He speaks and grins and leans in close. I find his manner infectious, and so I also lean forward. On a few occasions, our noses nearly rub.

“There are millions of genetic variations in the human body,” he tells me, as if discovering this fact for the first time. “However, if just one of them mutates – just one of them . . . ” Schneider claps his hands. “Bang!”

He doesn’t stop. “So in creating you, your parents provided two copies of each gene. This is the blueprint for every cell in your body. If the wrong combination comes together, you’re at a higher risk of cancer. Now, there are also environmental exposures that increase the risk. Maybe the well water you drank as a child. Living near a smokestack. Cigarettes, of course. If you’re genetically susceptible, environmental exposures can damage healthy cells. They start to look and act like cancer cells.”

Dr Bryan Schneider, a pioneer in the burgeoning field

of biologics, is tailoring cancer therapies to specific patients and tumour types. “We’re close to turning cancer into a chronic disease.”

Terrific.
And yet last year, US president Barack Obama expressed his aim to cure cancer “in our time”. A nebulous assertion, perhaps – nowhere near as specific as John F. Kennedy’s 1961 vow to reach the moon “before the decade is out”. End cancer in whose time? My grandfather’s? My son’s? Nonetheless, it’s a proclamation worth exploring.

So I’m here at Indiana University’s Melvin and Bren Simon Cancer Centre, in Indianapolis, one of America’s most respected cancer research and treatment centres. The centre attracts patients from around the world, as well as enthusiastic young physicians like the lanky Schneider, a wunderkind among experts studying the revolutionary cancer therapy known as biologics.

The centre is also the home of the legendary Dr Lawrence Einhorn, the oncologist who in 1974 actually cured one form of cancer – “cure” being the operative term in a field that both dreads and covets the word. Einhorn’s triumph was over testicular cancer, a pernicious disease that once killed 95 per cent of all men (predominantly young men) in whom it had metastasised.

Dr Lawrence Einhorn (far left) invented a revolutionary testicular cancer treatment. The first to be cured was John Cleland (left), otherwise known as patient zero. Cleland was 22 when he was told his cancer was terminal – 35 years ago.

But thanks to Einhorn and his team, Lance Armstrong is still racing, Pete Postlethwaite is still acting, Tom Green is still getting laughs and, by Einhorn’s own back-of-the-envelope calculation, since his cure more than 120,000 men once thought to be doomed have continued to lead fruitful lives. No other form of cancer has been eradicated in such a dramatic manner.

Schneider, an assistant professor at Indiana University specialising in haematology/oncology, clinical pharmacology and molecular genetics, would like to build on his mentor’s success. Today, we’re seated in his small office on the fourth floor of the centre, near the laboratory where he spends much of his workday.

“So, okay, here’s what I do,” he says. “I look at this puzzle of minor genetic variations that we all inherit, to see if they alter a person’s response to a given cancer therapy. As we’ve begun to unravel our genetic blueprint – the human genome – we’re starting to have a better understanding of how this machinery works. Ultimately, biologics will tell us who will develop cancer and who will benefit from a specific drug.

“Right now, the tumours are still outsmarting us. But are we close to turning all types of cancer from fatal diseases into chronic diseases – that is, diseases manageable enough that you will die of something else down the road? I believe we are close. Is that exciting or what?”
After all, if Einhorn could do it . . .

“Let me just say that when someone like Larry Einhorn comes along with a eureka moment like that, you take notice.”

Dr Len Lichtenfeld pauses to collect his thoughts. “I was doing my cancer fellowship back in the early Seventies, when certain forms of testicular cancer were almost uniformly lethal,” says Lichtenfeld, the deputy chief medical officer for the American Cancer Society’s national office. “I still vividly recall days spent in our small intensive-care unit taking care of men in their twenties. Sitting by their bedsides. Watching them pass. Then suddenly, out in Indiana, there was a doctor with a new drug for this serious, incurable disease.

“Einhorn’s work had far-reaching effects,” continues Lichtenfeld. “Curing the incurable. Giving hope to all cancer patients. It was remarkable.”

Even in his late sixties, Einhorn is still treating patients. Around his cluttered desk, the walls drip with testimonials, photos and thank-you notes from survivors (average age 25). A rubber Livestrong bracelet from Lance Armstrong’s cancer foundation is on his left wrist.

Cancer has been considered fatal since the dawn of organised medicine, says Einhorn. But it is only in the past two centuries that more-thorough autopsies, improved microscopes and modern science have determined that “cancer” is, in fact, “cancers”.

Oncologists have long known that localised cancer cells do not kill. No woman dies from a lump in her breast; she dies because the mutated cells in her breast spread to her lungs or other vital organs. When the symptoms are caught early enough, these abnormal cells can be removed surgically or treated successfully with radiation and/or chemotherapy. Once the disease metastasises, however, the odds of recovery plummet. In certain cancers (melanoma, pancreatic and oesophageal cancers, for instance), those odds hover near zero.

Until Einhorn’s dramatic discovery of the chemotherapy treatment Cisplatin, which is derived from the heavy metal platinum, no-one had been able to overcome the disease’s inevitable lethality. Ever. Today, cancer trails only heart disease in the number of people it kills – eight million globally every year. Medically, if you don’t first suffer a fatal stroke or heart attack, or aren’t hit by lightning, you will eventually die from one form of carcinoma or another. All it takes is one abnormal cell.

All this will change, however, as the medical community applies the information gleaned from the recently sequenced human genome. “That’s the job for the next generation – people like Schneider,” says Einhorn. “There has been an explosion in knowledge of what we call the collective biology of cancer.

“Soon enough, sometime in this century, medicine will cease labelling cancers by the organs they affect, but instead by specific genes,” he continues. “Mr Smith may have lung cancer where gene number 18 is abnormal, whereas Mr Jones may have lung cancer that looks the same under the microscope, but gene number 35 is abnormal. That’s when we’ll nail this thing. It’s all about biologics.”

Back in his office, Schneider explains that biologics are simply synthetic compounds, administered by IV or orally with tablets, built to disrupt a specific part of a cell’s daily function that has gone haywire. They can be composed of a variety of substances, including antibodies – which are usually made by the body to fight off infection. Once inside the body, biologics target fast-growing cancer cells exclusively, unlike the equal-opportunity, burn-’em-and-poison-’em radiation and chemotherapy.

The science of human genetics, Schneider reminds me, is still in its infancy. So naturally, the development of biologics remains semi-conceptual. But some of these drugs have already shown great promise. The biologic Herceptin, for instance, was created in lab mice to recognise and attack breast-cancer cells. A study published in the British medical journal The Lancet found that in one clinical trial, Herceptin significantly increased survival rates for 25 per cent of women with a certain type of early breast cancer. The drug has unresolved side effects, including the danger of congestive heart failure, which affected two per cent of patients in the trial. Nonetheless, it’s an exciting advance for the more than one million women around the world who’ll be diagnosed with breast cancer this year.

“And there are many more biologics in use or in development right now,” says Schneider.

Rather than crowd out older radiation and chemotherapy techniques, these new drugs will “play nicely” with the standard treatments, he adds. In his view, managing cancer is the objective, much as someone with diabetes manages their illness. And the more we discover about the human genome . . . “Well, soon the treatments of not too long ago will be looked at as the dark ages of medicine.”

Schneider continues: “Someday, and this day is fast approaching, we will figure out how to treat different cancers in different parts of the body with individual treatments based on each individual’s genetic make-up.”

In other words: it’s the genome, stupid.

“Precisely.”
Dr Douglas Schwartzentruber, grimaces at my wordplay. “And if we do this right,” he continues, “the discoveries coming from the genome will allow us – and have already allowed us – to approach cancer with molecularly targeted treatment.”

Schwartzentruber knows this better than most. He recently concluded an eight-year clinical trial on a vaccine for metastatic melanoma, one of the deadliest cancers. The vaccine not only shrank melanoma tumours, but also delayed their spread. His is one of the first studies to prove that vaccines might have a medical benefit against cancer. In May last year, Schwartzentruber presented his trial results at the annual American Society of Clinical Oncology convention. They became, appropriately, the talk of the conference. The results were no small thing, given that the World Health Organisation estimates about 48,000 melanoma-related deaths occur worldwide each year. Ninety per cent of victims succumb within five years of diagnosis.

I’ve travelled almost 300 kilometres north from Indianapolis to Goshen to see Schwartzentruber, a surgical oncologist and the medical director of the 11-year-old Goshen Centre for Cancer Care. The doctor is a tall, slender man with the delicate hands of a concert pianist. Before returning here to his hometown six years ago to head the centre, he served for 13 years as a senior investigator in the surgery branch of the US National Institutes of Health’s National Cancer Institute. He senses that I’m lost in the fog of medical terminology – Gp100 protein? T cell receptors? – and translates as best he can.

Take the word “vaccine”, for instance. The shot I received as a kid? “Not quite,” he says. “Most of the vaccines we’re familiar with are given to healthy people to prevent infectious diseases – polio and smallpox, for example. Here we’re talking about a therapeutic vaccine, as opposed to a preventative one, that’s administered to patients who already have metastatic melanoma. In layman’s terms, what we’re doing is gearing up the body’s immune system – supercharging it, so to speak – to recognise and go after specific cancer cells. And the results are, well, heartening.”

The biologic vaccine developed in Schwartzentruber’s multi-institution study mimics a fragment, or marker, of a specific protein found on the surface of a melanoma cancer cell. Administered alongside the immune-system-boosting therapy interleukin-2 (another molecular biologic, also used to treat kidney cancer), the combination stimulates the body’s white blood cells to seek and destroy that specific marker and therefore the cancer cell.

Schwartzentruber’s trial found that melanoma tumours treated solely with interleukin-2 shrank by 10 per cent. When combined with the vaccine, the shrinkage more than doubled, to 22 per cent. The patients lived an average of 20 weeks longer.

Despite this major advance, Schwartzentruber, like Schneider, isn’t ready to walk away from traditional treatments such as radiation and chemotherapy. He, too, cites Einhorn’s chemo work with testicular cancer as a motivating factor. “I remember thinking, ‘Wow, we can cure one cancer, why not all?’.” And he mentions advances in diagnostic apparatus, from CT scans to MRIs to state-of-the-art PET scans, as keys to future eureka moments.

“Imaging has been one of the most significant advances in cancer care over the past five years,” he says. “We have much better ways of spotting it early now.”

He swivels in his chair to summon to his computer screen duelling images of a diseased kidney. The first is a two-dimensional computerised tomography, or CT, scan. The second is a three-dimensional positron emission tomography, or PET, scan.

“See here?” He moves a ballpoint pen across the screen to highlight the inflammation, which is much more clearly defined in the second image – like looking at a child’s crayon drawing and then a draftsman’s blueprint. “When we find the cancer early enough, this allows the radiation to really pinpoint and attack the problem, without what you might call collateral damage to healthy parts of the body, or even healthy parts of the same organ. Which, in turn, allows a patient to receive more radiation directly to the affected areas.”

Schwartzentruber turns away from the screen. “Unfortunately, all this stuff is expensive. One of the keys to beating this disease is finding ways to keep costs down. I don’t have an answer for that.”

Next for Schwartzentruber’s team is a larger clinical trial. The goal: “Our challenge is figuring out why this vaccine is working only 22 per cent and not 100 per cent of the time.” He reels off the names of half a dozen melanoma researchers, clinics, labs and hospitals working with him towards that goal.

“We’ve come this far, and we’re all asking ourselves, ‘What’s next? How do we get to the next step?’.

These are all questions that fuel our research.”

Someday, perhaps soon, could we have a preventative vaccine against not only melanoma, but all cancers? Schwartzentruber laughs. Reporters with their time-machine fantasies.

“That’s a long way off, and I don’t know if we will ever get to a totally preventative vaccine. But . . . ” He pauses. “Can we alter the genes and prevent that cancer cell from mutating?” He appears to be thinking out loud. “What drives it to change in the first place? Once we understand what the change is, can we find ways to not only reverse it, but prevent it, too? Maybe.”

He dares not utter the word “cure”. Cancer researchers insist that the best treatments can be enacted only incrementally – there are no silver bullets. And Einhorn’s testicular cancer breakthrough notwithstanding, this is what we have generally seen since another US president, Richard Nixon, declared war on cancer almost 40 years ago. It was a war run by a committee that apparently never meets.

So forget cure. How about being personally “excited” about the vaccine and its future?

Schwartzentruber’s face reddens. The corners of his mouth turn up, just slightly. “In this business it’s a slow path. Cautious optimism. We’re not there yet. Baby steps.”

C’mon, doc. Give it to me straight. Excited or not?
“Okay. Yes. Very excited.” The wide smile finally bursts through.
“Okay, extremely excited. I can’t lie.”

The vast and venerable Mayo Clinic is what the Goshen Cancer Centre wants to be when it grows up – just give it another century. At least these are my thoughts as I weave through the scores of Mayo Clinic buildings – hospitals, libraries, laboratories – that dominate its hometown, the small city of Rochester in Minnesota.

Conversely, and buzz-killingly, I am also thinking about prostate cancer.

Prostate cancer is the second most diagnosed cancer globally. In 2007, 780,000 men were diagnosed with the disease; 250,000 died. It also remains one of the most mysterious cancers to treat. Despite prostate cancer’s prevalence, science has yet to determine its “profile” – that is, why some forms remain dormant while others spread and turn lethal. So men diagnosed with various stages of the disease can opt for dozens of treatments, from wait-and-see monitoring to different forms of radiation, medical treatments or surgery. Incredibly, at present, no-one can say for sure which of these is the best course.

It’s not terribly uplifting news, considering that this is one of the most ubiquitous of cancers. As Lichtenfeld said, “Show me a healthy, clean-living senior citizen with nothing else wrong with him and I’ll show you some form of cancer somewhere in that body.”

Dr Eugene Kwon may have discovered the Holy Grail of prostate-cancer treatment: a drug that completely eradicated the cancer in four of his patients.

To which Dr Eugene Kwon now adds, “If Dr Lichtenfeld was referring to men, he was most likely referring to prostate cancer.”

Kwon, a urologist and immunologist at the Mayo Clinic, specialises in cancer research. In 2009, his team announced what could be the Holy Grail of prostate cancer treatments: an immunity-boosting drug that eradicated nearly all vestiges of prostate cancer in four patients who had a metastasised form that was considered inoperable.

A layman’s synthesis of Kwon’s breakthrough goes like this: when certain immune cells rush to combat prostate cancer, the cancer cells have an innate ability to neutralise them. “Think of the cancer as being able to flick the ‘off’ switch on these immune cells,” says Kwon.

Over the course of their study, Kwon’s team recruited 108 volunteers with advanced prostate cancer.

Half the group were given standard hormone treatments, which are proved to temporarily slow but not eradicate prostate cancer. The other men were given the experimental biologic agent ipilimumab – which prevents cancer cells from switching off the immune cells – in addition to the hormone.

The four men whose cancers vanished were in the latter group. In one case, a golf-ball-size tumour invading the patient’s bladder totally disappeared and only microscopic deposits of cancer were left in his prostate – making surgery an option again. Before the trial, these men had life expectancies of about 18 months to two years. Afterwards, they were pronounced cancer-free. (But not cured, of course.)
Kwon’s biologic was developed in mice that had been genetically manipulated to produce human antibodies capable of stimulating an immune response to prostate cancer and other malignancies. Like Schwartzentruber’s melanoma vaccine, and like the breast-cancer-fighting Herceptin, the experimental drug could not have been developed without the human genome. “Genomic research is to the 21st century what the microscope was to the 19th,” says Kwon.

After we settle into chairs in an empty lecture hall in the Mayo Clinic’s main clinic, I quickly get down to business: can you compare your discovery to Einhorn’s silver bullet for testicular cancer?

The customary circumspective preamble begins, with phrases like “incremental steps” and “cautiously optimistic”. But then Kwon flicks a shock of thick, black hair from his broad forehead and leans back in his chair.

“But to answer your question, yes, we think we’re at the very beginning of something like that,” he says. “We’ve had experiences with four patients now – responses that we simply have never seen before.

At one point, the pathologist asked if we were certain that we were sending him samples from the correct patient. He was shocked that the disease had just disappeared like that.”

Kwon’s team continues to monitor the remaining patients in the trial. “This study’s not done yet,” he explains. “Some of the patients are not even to the cycle where they receive the biologic.”
So when will this miracle drug hit the market?

Kwon holds up two hands, palms out. Slow down there. “We don’t know. We’ve since discovered that the amount of drug we used in this trial is one-third what we now know is the optimal dose.” So Kwon and his team are organising another study to administer the higher dosage.

“So perhaps one of these days . . . ” his voice trails off.

Yes? Yes? One of these days what?

“Well, we’ve managed to pull it back from the pelvis, the bladder, the places this cancer metastasises to. The next step is to kill the cancer completely where it lives, in the prostate. One day, surgery to extract the microscopic remains will not even be necessary. It will be gone. That’s the goal.”
So, when?

Kwon begins to say something, then catches his tongue. “I don’t want to jinx myself.”

He reconsiders. “We’ll probably know in the next couple of years, okay? We still need more trials and higher rates of response. This is a completely novel approach. I think we have learnt a phenomenal amount about cancer in the past 20 years. It’s much more complicated, much more sinister than we ever anticipated.

“However, we’ve also learnt which treatments might be possible and which are unrealistic. Unrealistic is having expectations that someone is going to discover one silver bullet – natural, nontoxic, no side effects, inexpensive, tastes great – that is going to melt away all cancers. Which I think is what the public wants. I believe we need to reach for a machine gun that fires multiple silver bullets at the cancer.”

He pauses, then adds, “You asked me when we first met if I consider our observations the Next Big Thing. I can only think of a quote by [composer, actor and wit] Oscar Levant: ‘Happiness isn’t something you experience; it’s something you remember’.

“Our work here isn’t the last step along the pathway,” he concludes. “May I ask you to come back and see me in a few years, to see what we have then?”

I had assumed that my lack of understanding about the technical minutiae of cancer and cancer therapies had bottomed after meeting Schneider, Schwartzentruber and Kwon. But Paul Grayson’s explanation of cellular biologics – stem-cell treatments – makes my teeth hurt.

“You see,” he says, “by inducing a ‘forced’ expression of certain genes, we can typically derive from an adult somatic cell – that is, a non-pluripotent cell – induced pluripotent stem cells, or IPSCs. You see?”

Uh . . .
“Let me put it another way. We might take a skin cell from a leukaemia patient and turn it into a healthy blood cell.” Oh!

“These are the fascinating things you can do with stem cells,” continues Grayson. “They can turn into any tissue in the human body.”

Grayson is on the phone from Barcelona, where, as the president and CEO of Fate Therapeutics, a US biotech company specialising in stem-cell therapies, he is attending a meeting of the International Society for Stem Cell Research. I called him to ask about Schwartzentruber’s ultimate goal of being able to launch a preemptive attack on cells destined to mutate into cancer. This is stem-cell territory of the future – the near future, as it turns out.

During embryonic development, explains Grayson, stem cells can take several pathways, including two so-called “rogue” pathways: cancer-enabling and cancer-causing. Rogue pathways have been implicated in multiple types of cancer-cell proliferation. “If we can shut off these pathways as the cells develop, we can change the characteristics and even the function of the cells,” says Grayson. “And, of course,
we can potentially make the cells less malignant.”

Grayson’s company is collaborating with the Dana-Farber Cancer Institute in Boston in the early stages of a clinical trial that will use stem cells taken from donor umbilical cords to treat leukaemia patients. Once implanted in patients, the cells should multiply quickly, vastly increasing the number of healthy blood cells (to box out the cancer cells) and immune cells (to attack the cancer).

But there are two other promising ways stem cells can be utilised in the fight against cancer, says Grayson. The first: creating healthy stem cells by transforming one type of stem cell into another for the same patient. Taking a skin stem cell, for example, and turning it into a blood cell. “That’s a new development in the field of stem-cell biology,” says Grayson, “and its application is a little bit further off.”

His second example hits the core of Schwartzentruber’s daydream: catching the potentially cancerous stem cell before it embarks upon a rogue pathway and turning it into a cell type that is not diseased.

“The key is to turn down the cancer machinery in the cell,” says Grayson. “It might sound far-fetched, but if you were to travel back in time a decade, a lot of what we’re doing today might sound far-fetched. The tools, particularly the sequenced human genome, just weren’t available to determine which genes are turned on in which cells, or which proteins that come from those genes are normal or abnormal – and may actually be causing some of the disease. Imagine turning nascent cancer cells into cells that are no longer cancer cells. That will be a new paradigm.”

The word “paradigm” is overused, but in this case it seems appropriate. If any of these remedies can merely eliminate the pain and toxicity of radiation therapy and chemotherapy, we will have certainly at least started down the runway to President Obama’s great leap towards a cure for cancer. Or, as another statesman once said in another context: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”

Winston Churchill was speaking about the British forces’ World War II victory at El Alamein.

Nonetheless, a war is a war is a war.

“Our recent advances are having far-reaching effects,” Lichtenfeld had said. “They’re encouraging other research. They’re exciting the medical community. For the first time, I’m thinking maybe not in my lifetime, but perhaps in my children’s lifetime, we can beat this thing.”