Singles, Grand Slams, and Losing the War on Cancer

The recent issues of Newsweek and TIME both carried sobering articles about the state of cancer research. Newsweekâs Sharon Begley reports that cancer is on track to claim 565,650 lives in the U.S. this year, and that number isnât a whole lot better than it was in 1971, when President Nixon signed the National Cancer Act and made âthe conquest of cancer a national crusade.â

Using age-adjusted figures, 199 out of every 100,000 Americans died of cancer in 1975; in 2005, it was 184 per 100,000. Much of the decline is due to improved survival rates for breast and colorectal cancers, and those successes come from earlier detection as well as advances in treatment. (One success that doesnât show up in the statistics is the interventions that have reduced cancer patientsâ suffering, which is important from a quality-of-life standpoint.) As TIMEâs Bob Saporito points out, though, several forms of cancer â including pancreatic, lung, and brain â âare still nearly invincible.â Begley also cites rising death rates for lung cancer, melanoma, and liver cancer.

There are reasons why cancer is harder to beat than other diseases; for one thing, itâs actually dozens of different diseases. "By the time there are 10 cancer cells, you probably have eight different cancers," one scientist tells Begley. Tumors can use several different pathways to grow, and drugs typically close off just one at a time. Most research is conducted by transplanting human tumor cells into mice, but those tumors almost never metastasize the way they do in humans. (Read all of Begleyâs article for details on these, and for the evolution in how scientists think about attacking cancer.)

The problem that both Begley and Saporito zero in on, though, is the way cancer research is conducted.

Much of the grant money funding cancer research comes from the National Cancer Institute. The overall amount of funding is a problem â Saporito notes that NCI funding has been flat for the last three years, and the cost of research has grown faster than inflation â but the way itâs distributed is also an issue. Begley sums up a common criticism: âinnovative ideas, ideas that might be grand slams but carry the risk of striking out, are rejected by NCI in favor of projects that promise singles.â She gives a couple of examples of how this has played out:

In 1984, backed by private funding, [UCLA's Dennis] Slamon found that 27 percent of breast cancers contain extra copies of [the gene] HER2. Over the next decade he and other scientists showed that HER2 caused the cancer, rather than being an innocent bystander (or "marker," as scientists say). They also found an antibody that attaches to HER2 like a squirrel's nest on a TV antenna, preventing it from picking up signals. In 1998 the FDA approved that antibody, called Herceptin, for use in breast cancers fueled by HER2. It was stunning proof of the principle that drugs could be precisely crafted to cripple molecules that lie upstream of cell replication, stoking the growth of cancer cells and only cancer cells, not healthy ones, and has cured thousands of women. After the 1984 discovery, NCI was happy to fund Slamon. "It was only because we had already shown that the research would work," he says wistfully. "It is, shall we say, a conservative way to spend your money." the very year that Nixon launched the war on cancer, an unknown biologist named Judah Folkman published a paper proposing that metastatic cells survive, and become deadly, only if they grow blood vessels to keep themselves supplied with nutrients. That process is called angiogenesis, and it had nothing to do with the genes and proteins that the soldiers in the war on cancer were fixated on. Throughout the 1970s "the reaction was mainly hostility and ridicule," Folkman (who died earlier this year) recalled to NEWSWEEK in 1998. "People would ask me [at scientific meetings], 'You really don't believe that, do you?' " NCI turned down his request for funds to continue his work, calling his ideas about the importance of angiogenesis in metastasis "just your imagination," Folkman said. He persisted, of course, laying the groundwork for what would become anti angiogenesis drugs. Avastin was approved for colorectal cancer in 2004.

Begleyâs article also includes some discussion of why hitting singles can be a worthwhile strategy. The cure rate for childhood cancers has soared because pediatric oncologists collaborated, enrolled 80% of their patients in clinical trials, and âthrew everything in the existing medicine chest at the problem, tinkering with drug doses and combinations and sequencing and timing.â The relative simplicity of childhood cancers probably helped this approach succeed, but itâs an example of how plugging away at a problem, rather than seeking a silver bullet, can work. There are also plenty of examples of discoveries that looked like they might be big breakthroughs but ended up fizzling in human trials.

In addition to the distinction between âsinglesâ and âgrand slamâ research, thereâs also a distinction between research designed to add to our knowledge about cancer vs. research aimed at developing a treatment. Saporito describes two charities that are specifically pursuing treatments:

SU2C [Stand Up to Cancer] will not distribute funds to research institutions. Instead, it will assemble dream teams of scientists across disciplines and institutions, and they will work collaboratively on projects designed to deliver a product of sorts--as opposed to an academic paper--within a defined time period. Says [SU2Câs Laura] Ziskin: "They can only get funded if they can produce a treatment."

To vet and choose the projects, SU2C has recruited a high-powered scientific advisory committee chaired by Phillip Sharp, a Nobel Prize--winning cancer researcher at MIT. The selected projects will then be monitored by the American Association for Cancer Research. "What I hope to do is identify areas where we could accelerate progress, particularly in areas where there's need--ovarian, pancreatic, glioblastoma," says Sharp.

Additionally, 20% of the funds raised will go to higher-risk projects with potentially greater paybacks. It's a science version of throwing it long. "If you run the same play every time, you're not going to win the game," says Armstrong. One of SU2C's advisers was the late Judah Folkman, a famed cancer scientist whose pathbreaking theory that tumors grow via angiogenesis (creating their own blood supply) was resisted for decades. "There may be other Judah Folkmans out there," says Ziskin. "We don't want them wandering around for 40 years."

SU2C is not the only independent group shaking things up. The Multiple Myeloma Research Foundation used a pay-for-results funding model that has more to do with Silicon Valley than Big Pharma to support research that in four years got four new treatments to patients--Thalomid, Velcade, Revlimid and Doxil. That's about six years faster than the decade it usually takes for such drug development and rollout. Multiple myeloma is a rare cancer of the bone marrow that sickens about 20,000 Americans each year--precisely the uncommon form of the disease that often falls into the research cracks. The MMRF benefited from the aggressive work of founder Kathy Giusti, a multiple-myeloma survivor and former pharmaceutical executive. When she and her group first raised enough money to start funding research, she faced a feeding frenzy of research applicants. "They will do what they have to do to get grant money. They're desperate," she says.

Orac, the cancer surgeon/scientist who blogs at Respectful Insolence, comments on this new funding development:

Still, my skepticism aside, I do think that more chances need to be taken, and there need to be funding mechanisms in place to support taking more chances. The NIH definitely rewards caution and punishes innovation, its claims otherwise notwithstanding The problem is finding the balance that results in the most efficient translation of basic science into effective cancer treatments. Unfortunately, lately, in this effort, I sense a denigration of the difficult, painstaking research that goes into characterizing the molecular mechanisms that need to be characterized before researchers can design these new bang-up therapies and a glorification of seemingly "risky" (translation: "sexy") newer approaches. Whether that glorification is justified remains to be seen. In the meantime, I welcome attempts to shake up the current research funding paradigm. I just don't share the faith that the new boss will necessarily be any different than the old boss.

If striking the right balance between singles and grand slams seems tricky, the picture becomes even more complicated when you add the crucial-but-difficult component of prevention. Begley tackles this one:

Both presidential candidates have vowed to support cancer research, which makes this a propitious time to consider the missed opportunities of the first 37 years of the war on cancer. Surely the greatest is prevention. Nixon never used the word; he exhorted scientists only to find a cure. Partly as a result, the huge majority of funding for cancer has gone into the search for ways to eradicate malignant cells rather than to keep normal cells from becoming malignant in the first place. "The funding people are interested in the magic-bullet research because that's what brings the dollars in," says oncologist Anthony Back, of the Hutch. "It's not as sexy to look at whether broccoli sprouts prevent colon cancer. A reviewer looks at that and asks, 'How would you ever get that to work?' " And besides, broccoli can't be patented, so without the potential payoff of a billion-dollar drug there is less incentive to discover how cancer can be prevented.

Another missed opportunity involves the environment around a tumor cell. "We used to focus on cancer cells with the idea that they were master of their own destiny," says MIT's Weinberg. "By studying genes inside the cell we thought we could understand what was going on. But now [we know] that many tumors are governed by the signals they receive from outside"âfrom inflammatory cells, cells of the immune system and others. "It's the interaction of signals inside and outside the tumor that creates aggressiveness and metastasis."

Which leads to the third big missed opportunity, the use of natural compounds and nondrug interventions such as stress reduction to keep the microenvironment inhospitable to cancer. (Cancer cells have receptors that grab stress hormones out of the bloodstream and use them to increase angiogenesis.) "Funding has gone to easier areas to research, like whether a drug can prevent cancer recurrence," says Lorenzo Cohen, who runs the integrative care center at M. D. Anderson. That's simpler to study, he points out, than whether a complicated mix of diet, exercise and stress reduction techniques can keep the micro-environment hostile to cancer. And while we're on the subject of how to reduce mortality from cancer, consider these numbers: 7 percent of black women with breast cancer get no treatment, 35 percent do not receive radiation after mastectomy (the standard of care), and 26 percent of white women do not. As long as scientists are discovering how to thwart cancer, it might make sense to get the advances into the real world.

Really doing prevention right will require lots more money â not only for unsexy research on broccoli, but for a better healthcare system that can provide early detection and treatment to everyone, not just those who are insured and can afford the copayments and deductibles. And if we really want to uncover and address a wide range of carcinogens, weâre going to need the political and financial resources to withstand attacks from companies whose products are or could be contributing to cancers. The drop in lung cancer deaths is one of the success stories of recent decades, but we were only able to achieve it after spending huge amounts of time, money, and attention countering the tobacco industry.

In short, weâre not winning the war on cancer, and weâre not positioned to do so any time in the future. More research funding and better systems for distributing it will help, but we as a country also need to make health more of a priority.

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