MONOLOGUE 24

Cancer is just as deadly as it was 50 years ago. Here's why that's about to change.

Why haven't we cured cancer yet? It seems like almost every day, we hear about another miraculous advance in cancer treatment. Drugs that cause tumors to shrink,gene therapies, and even a possible vaccine. And yet, our loved ones keep dying of cancer.

We spoke to cancer experts to find out why the death rate from cancer hasn't changed in the past 50 years — and we learned how genetic therapies could transform cancer treatments tomorrow.

Top image: Juan Gaertner/Shutterstock.com

Most of us have lost friends and loved ones to cancer, and we're all familiar with the inexorable logic of tumor growth and metastasis. It's a disease so horrible, it defies metaphor - people use cancer as a metaphor for the worst things in life, but there are no metaphors dreadful enough to describe cancer.

So it's hard not to get your hopes up when you hear about miraculous breakthroughs. And sure, to some extent, the news media (and press releases) tend to over-hype these encouraging developments. But still, it feels like we're constantly getting new hopes for either revolutionary cancer treatments, or a "magic bullet" to stop all cancer.

And when these hopes don't materialize, we wonder who's to blame. Did greedy drug companies hold back a promising treatment? Did an overzealous FDA kill a wonder drug? Did cancer specialists refuse to accept new ideas? Or is cancer just too smart for us?

Apparently, it's mostly the last one. Cancer is a lot smarter than we ever realized.

"We grossly underestimated the cleverness of cancer"

Medical science has made incredible advances in our lifetimes — but one sobering truth remains. "If you look at the death rate from cancer, there's no dramatic change over the last five decades," says David Agus, author of The End of Illness and the head of University of Southern California's Westside Cancer Center. "There are little wins, but no dramatic change."

On the plus side, the incidence rate of cancer has gone down somewhat, as fewer people smoke and some obvious carcinogens have been eliminated from the environment.

It's true that we've learned a lot more about cancer in the past 50 years — but mostly what we've learned is that cancer is a lot more complicated than we thought.

"We truly grossly underestimated the cleverness of cancer," says Ralph deVere White, director of the U.C. Davis Cancer Center. We're sequencing the genomes of many cancers, and what you discover is that "regrettably, they have many more molecular changes than we ever saw."

Dr. White adds that we've learned more about cancer in the past 10 years than we had learned in the previous 2000 years. "Cancer never allowed us to get so much information to address our inadequacy." And now, the challenge is to "turn that data into knowledge," which requires a lot of cutting-edge bioinformatics. (Too bad everybody's funding is being cut right now, at a crucial time in cancer research.)Melanoma image via National Cancer Institute.

You probably already know that cancer is not just one disease — it's many diseases, gathered under a single umbrella. But in the past, we thought there were types of cancer called "breast cancer" or "prostate cancer," which were basically site specific — and now we've found that cancer is much more varied.

"Cancer is hundreds if not thousands of different diseases," says David Weinstock, an assistant professor with the Dana-Farber Cancer Institute and Harvard Medical School. "Saying, 'Why don't we have a cure to cancer,' is like saying, 'Why don't we have a cure to infection.'"

There are multiple levels of complexity, adds Weinstock: You have different basic types, like colon cancer versus lymphoma. Then you have hundreds of different types of lymphomas, and then every single person's lymphoma is different at a molecular level. And even though you think of cancer cells as all identical, in fact "not every cancer is the same, [and] there are many differences within a tumor." When you attack a tumor, "you're killing a diverse population" of cells, some of which will be resistant.

Most cancers under treatment have 100 different mutations within a single tumor, says Agus. "It's very hard to model that."

Meanwhile, you have to kill the tumor without killing the person who has it. People talk about the "therapeutic index," says Weinstock — which is the chances of killing the tumor, versus the chances of killing a normal cell.

Another wrinkle: cancer cells are bi-directional, meaning that stem cells can differentiate into mature tumor cells — but mature tumor cells can also turn back into stem cells, says Agus. Thus, treatments that have involved just killing the stem cells in the hopes that this would keep the cancer from recurring have failed, because the tumor can always repopulate with more stem cells.

The hype, and why so many drugs fail

"I can't imagine anything more heart-wrenching than believing that you or a family member could be helped by something out there but you can't get it," says Weinstock. The FDA is in a difficult situation, he adds, because "they want to be as aggressive as possible in allowing people to have access to as many drugs as possible."

There's a misconception that the FDA is a bunch of bureaucrats, making arbitrary decisions based on politics — but Weinstock says it's actually "people like me, academics and scientists and clinicians, who get asked to serve on committees... and the overwhelming majority of the time, the FDA goes along with [our] decisions." Image viaNephron.

There are plenty of drugs that do a great job of shrinking tumors in mice, but turn out not to be suitable for humans, adds White. "Obviously you're excited [when a drug works on mice]. But the problem is that 95 percent of those new drug applications fail. They don't get FDA approval. 70 percent of them fail in that Phase One, which is the toxicity study. That leaves with you with 30 percent. And then 60 percent of those fail, and [most] of the time, it's because they don't work. That's nobody's fault. It isn't surprising that progress is slow."

"It's a tragedy when the drug is toxic and hurts people, and it's almost as tragic when the drug doesn't work," says Weinstock. "We've seen that recently with Avastin," which had its approval for breast cancer revoked.

"Very good people and very smart people spend their life trying to beat this disease," says White. "So every time you see a glimmer of hope, you hope that this is the great breakthrough... and obviously that gets hyped." Part of this is because you constantly have to seek more funding for your research, and everyone from members of Congress to your peers want to fund research that looks exciting. And then, of course, there's the media — and we certainly tend to get over-excited as well.

What about a cancer vaccine?

There's been a lot of talk in the last month about the idea of a targeted vaccine for cancer — either a therapeutic vaccine, to cure existing tumors, or a prophylactic one. The idea of triggering your own immune system to fight cancer is an exciting one.

But Agus says that we've been trying to create vaccines for cancer for a hundred years, "and it has yet to work." Unlike smallpox, where there were patients who were cured on their own, "there are no patients with advanced metastatic tumors who have them go away on their own." So the idea of a vaccine "goes against a hundred years of history." Image: Anti-Cancer Antibodies, via Pacific Northwest National Laboratory.

But actually, some renal cancers do have a spontaneous rate of remission, notes A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, whom I had coffee with the other day. And there is a compelling reason to believe that one day the immune system could be triggered to attack some cancers — and that's the fact that some cancers only affect people whose immune systems are already compromised.

The obvious example of this is people with AIDS, who develop Kaposi's Sarcomas. If you restore their immune systems, "the Kaposi's will melt away," notes Sartor. Also, people who have been on immunosuppressive drugs following an organ transplant are more at risk for certain cancers, and if you can restore the immune system, the cancers tend to be reduced.

Finally, Sartor points to the success of therapies like Interleukin and Provenge, which rely on the immune system to attack leukemia and prostate cancer, respectively.

Genetically targeted therapies

So yes, the fact that we've been able to sequence the genomes of tumors has made us realize they're much more complex than we ever knew. But we are also slowly starting to develop more genetically targeted therapies – the trouble is, so far these are only targeted at cancers that don't affect a huge number of people.

According to Weinstock, the Dana Farber Cancer Institute has a program called "Profile," which involves looking for a list of commonly mutated genes, to see if those genes are mutated in someone's specific cancer. Eventually, he'd like to see more of the common mutations sequenced and identified, so "we'll be able to say exactly what genes are defective in someone's tumor."Image via Andres Perez.

And once you know what mutations someone has, you can probably figure out which signaling pathways are affected by those mutations, and target those, says Weinstock. For example, if you know someone has a problem with a particular gene, you may know that you can use a specific type of kinase-inhibitor on that patient, to block the enzymes that are involved.

For example, says White, we now have drugs that specifically address mutations in the EGFR receptors. If you happen to have that specific type of cancer and you take the drugs that block those receptors, "the tumors just melt away." Also, there's herceptin for some breast cancers, TKI inhibitors for renal cancer, or MDV3100 for prostate cancer.

"These [drugs] are driven against molecular events," says White. There's also been a shift in the mindset of drug companies, which used to prefer cancer drugs that could be aimed at a wide swathe of patients, to sell lots of drugs. Now, companies are learning that drugs that are very specifically targeted at one relatively tiny population of cancer patients can still make plenty of money.

"I would anticipate the number of drugs we have 50 years from now will be astronomically larger than today, and those drugs will be used in a much more targeted fashion," says Sartor. Instead of a single treatment for breast cancer, we'll differentiate it into "100 different types," each with its own therapy.

"It wasn't very long ago [that] Steve Jobs spent $60,000 having his cancer sequenced," says White. But by next year, there will be a machine available that will do the same thing for $1000 a pop.

More like weather systems

Agus is a huge proponent of treating cancer less like a disease, and more like a weather system, which can be mapped and hopefully controlled.

"I see it almost going towards things like climate-modeling," says Agus. "A climate modeler goes and looks at the shape of the clouds, and looks what's going on wind-wise and the temperature and so on, and then makes predictions. I want to be the same, where I can look at multiple variables, whether it be the sequence, what the proteins are, what the host is doing [and] the shape of the cancer. All of those things together, you can start to make accurate modeling and predictions."

It requires thinking more like an engineer — and in fact, Agus is working with physicists and engineers on this, including string theory pioneer Murray Gell-Mann and supercomputer pioneer W. Daniel Hillis.

Sometimes instead of only attacking the tumor directly, the best approach includes also making changes in the host. For example, says Agus, doctors have discovered that they can give breast cancer patients "a drug that builds bone, an osteoporosis drug, and it will reduce the recurrence by 30 to 40 percent. So the notion is, if you change the soil, the seed doesn't grow as well." Image viaDione Silva.

Sartor says that instead of attacking cancer cells, you can pursue treatments that "are targeted to the tumor microenvironment," such as "anti-angiogenesis compounds, that bind to blood vessels, which are common to a number of tumors." Sartor calls this "stroma-targeted therapy," and says it could target many types of tumors by cutting off their blood supply.

Given the huge genetic diversity even within individual tumors, the approach of targeting the stroma, or connective tissue, has a certain advantage. "The stroma is typically more stable, and if you can effectively target a tumor's stroma, you don't have the same mutation machine that exists in cancer cells," Sartor says. He calls cancer cells "Darwinian machines," because if you attack one type of cell, you're actually selecting for treatment-resistant cells. This is one way around that problem.

Agus would also like to see more focus on simple prevention methods — like, if you take an aspirin every day for 10 years, it reduces your chances of dying of cancer by double digits. Not to mention simple changes in people's behavior.

"Galileo would go every night and map all the stars in the sky, and after four months he could tell you where every star was. But he didn't know what a star was," says Agus. "We may not quite understand what cancer is, but our job is to control it. It's a little bit different parameters."

Will we one day look back on chemotherapy and radiation therapy as barbaric?

I've heard people say that before – that 50 or 100 years from now, the idea of giving people poisons and radiation to get rid of cancers will be seen as barbaric or bizarre. Weinstock says this is certainly possible. "I'm a medical oncologist. I give chemotherapy, I think radiation is kind of crazy, right? You're basically just taking a beam of radioactive energy and focusing it on an area.... I hope that 100 years from now yes, we look back and say all the stuff we're doing now is barbaric."

On the other hand, radiation therapy may actually be becoming more successful. When I spoke with Dr. Sartor, he was in San Francisco presenting a paper at an oncology conference about Radium-223, an element that he says will "kill pretty much any cancer you aim it at." As of now, it's limited to use in osteoplastic bone metastasis, but if we learn how to target it with other types of cancer, it could have a huge application.

Like some of the other doctors I spoke to, Agus wants to see cancer become more like a chronic disease, like diabetes. And as part of that, he wants to see a shift in mindset that goes along with referring to cancer as a verb, instead of a noun: "You're cancering.