Diana Steele

Finding a new anti-cancer drug is a little like looking for a needle in a haystack. Scientists have to look through a lot of hay before they find something that looks anything like a needle. 

But if you do have to look for that needle, it helps if you can look at thousands of pieces of hay at once, rather than sifting through one-by-one. 

In drug discovery these days, robotic machinery helps to do the sifting in a technique called “high-throughput screening.” This can be used not only to find potential drug candidates, but also to look for genes important in cancer.

Until the 1990s, most drugs were found by isolating natural products — organic molecules produced by plants and animals that were discovered to have some desirable biological activity in humans. Unfortunately, the molecules are often large, complex and difficult to synthesize in a laboratory, which is a problem if the drug comes from a rare natural source. Taxol, for example, later patented as an anti-cancer drug, was isolated in the 1960s from the bark of the Pacific yew tree. Demand for the drug led to concerns about environmental effects of harvesting the endangered trees &mdash; until scientists developed a semi-synthetic method for making the drug in 1993. 

Instead of continuing to run into problems trying to copy nature’s handiwork, “someone came up with the idea that you could bypass all those difficulties if you just made a whole lot of simple compounds that are easy for an organic chemist to make,” says biochemist Michael Roth, PhD, “and then screen through these very large arrays of compounds to find one that has biological activity.”

For high-throughput screening, chemists make “libraries” of thousands, hundreds of thousands or even millions of compounds. Roth, who directs the high-throughput screening lab at the University of Texas Southwestern Medical Center at Dallas, says he assembled a library of 200,000 compounds purchased from various pharmaceutical companies; first looking through their catalogs of compounds using software tools to see which ones were most likely to have drug-like activity.

Then biologists develop an assay, a screening tool to look through the library for a particular type of biological activity. Because the experiment has to be performed a hundred thousand to a million times, it has to work on a very small scale — about the size of one drop from an eyedropper. 

Unfortunately it’s a little like looking through the haystack and finding a few things that might eventually be able to be used as a needle: a lump of metal, a stick with an eye, or something with a sharp point.

 “Natural products are produced by millions of years of evolution so that they are really designed to do exactly what they do,” Roth says. “And these random compounds are not.”

But because the synthetic compounds are easy to make, they’re also easy to modify. A typical assay might come up with tens of would-be needles. Chemists alter the compounds and screen them again to see whether the changes have made them more active.

A case in point is the drug Nexavar, approved in 2005 for treating kidney cancer, and in 2007 the first drug approved to treat advanced liver cancer. 

Chemists from the pharmaceutical companies Bayer and Onyx screened 200,000 compounds starting in 1994, looking for any compound that could inhibit the activity of an enzyme called Raf kinase, which is important in cancer. They found several, says Hanno Wild, PhD, of Bayer HealthCare AG, based in Wuppertal, Germany. “There was one particular one which we thought was a good starting point for an optimization program,” Wild says.

The company ended up making about 6,000 variations until the one that eventually became Nexavar was developed. It was a thousand times more potent at inhibiting Raf kinase than the original.

High-throughput screening can also be used to hunt for disease-related genes, checking each of the 25,000 or more genes in the human genome.

In a study published in Nature last year, Roth and his collaborators found 80 genes that, when turned off, made a Taxol-resistant strain of cancer sensitive to the drug again. The hope is to eventually develop a drug that counters Taxol resistance, or devise combination therapies that prevent it from developing in the first place.  

Diana Steele is a freelance science writer based in Oberlin, Ohio. 

It's a little like looking through the haystack and finding a few things that might eventually be able to be used as a needle.

Articles

The massive search for new drug candidates, amid haystacks of possibilities.

Pinpointing Progress

An ugly, visible scar can be a difficult reminder of a cancer surgery. But even a hidden scar can be itchy, painful, or tight. 

Fortunately, surgical scars can be reduced or revised in a number of ways, from laser treatment that can reduce a scar, even years after it has formed, to effective over-the-counter therapies that are especially helpful in the early stages of scar formation.

“Scars can be an unwanted reminder to the person of the cancer that used to be there, opening up lingering questions for [a survivor] and adding to fears of a possible recurrence,” says dermatologist Rebecca Tung, MD, of the Cleveland Clinic. “That’s where dermatologists come in, to help alleviate these scars and remove any sort of stigma that they may have with them.”

The mode of treatment a dermatologist or plastic surgeon might select to improve a bothersome scar depends greatly on the age of the scar and what type of scar has formed, Tung says. 

The most cosmetically disfiguring scar, Tung says, is called a keloid—a firm, raised, red scar, resembling a cauliflower floret, which extends beyond the area of the original incision. These scars often itch and can be painful. Keloids can form anywhere on the body but are most common on the earlobes, chest, back, and shoulders, and occur more frequently on darker-skinned people. They can form weeks or even years after an incision. 

Another, less disfiguring type of scar is a hypertrophic scar, also usually a red or raised scar, but one that doesn’t extend beyond the border of the incision. Just like a keloid, it can be itchy or painful.

Both of these types of scars have too much scar tissue, which results from a healing response stuck in overdrive. The normal healing process brings inflammation along with extra blood vessels to a wound, and new cells that produce collagen to replace lost skin. But a hypertrophic or keloid scar develops when there’s too much collagen, “and then those initial inflammatory cells and blood vessels that come into play continue to hang around,” says dermatologist Tina Alster, MD. “You have all the troops in there, and then they just don’t clear out.”

Alster, who heads the Washington Institute of Dermatologic Laser Surgery and is a clinical professor of dermatology at Georgetown University in Washington, D.C., often uses laser treatment for hypertrophic or keloid scars. Lasers cause “just enough injury to get the process maturing in the way it should have normally,” she says, “to clear out those blood vessels, to cut down on the inflammation and to exert a negative effect on collagen growth.” Excess collagen contributes to the tightness of the scar.

The laser used to treat these types of scars is called a pulsed dye laser and emits light at a specific wavelength (585 nanometers) that is absorbed by the hemoglobin in red blood cells. The laser doesn’t cut or abrade the skin. “This laser treatment is really not uncomfortable at all,” says Alster. “During the treatment, there’s a bit of a snapping sensation, followed by the feeling of a sunburn. And right afterward, it may look a little pink and swollen, but there is no crusting, scabbing, or oozing.”

The treatment lasts only a few minutes, depending on the size of the scar, and then it takes about six to eight weeks for the area to fully heal, although it may only be slightly reddened for a few days. Most people need two or three treatments, two months or so apart, before they see significant improvement in a scar. “Two to three treatments,” says Alster, “will improve a scar an average of 50 to 80 percent.”

Of course, patients can keep getting laser therapy if they want to see scars improve even more, but the last 20 to 50 percent is harder, she says, and no one will ever have a scar disappear. But because laser light is non-ionizing radiation, “it does not change cell structure in any malignant way. It’s safer than going out in the sun for half a day,” she says. The more laser treatments are performed, she adds, the better a scar responds. The scar continues to flatten, becoming more pliable with an improved surface texture.

Given everything else that cancer survivors go through, this is the easiest and probably the happiest thing that they do.

The Cleveland Clinic’s Tung says laser treatment is often combined with cortisone injections, which also help damp down collagen production and decrease blood vessel formation. Often the first thing patients notice is that their scars are less symptomatic, she says. “Itching is reduced, there’s less pain, so overall, they’re much happier.”

“Given everything else that cancer survivors go through, this is the easiest and probably the happiest thing that they do,” adds Alster. “It makes them feel better, and they see the results very quickly.”

For scars, especially keloids, that don’t respond to laser treatment, surgical scar revision—or cutting out the scar&mdash;is an option. Treating the site afterward with prescription imiquimod cream, which affects the skin’s immune response, can help prevent the keloids from returning.

Hypertrophic and keloid scars are treated similarly, but they’re not the only type of scar. A third type of abnormal healing response leads to an atrophic scar, where there is not enough collagen in the area. The scar appears sunken or dimpled. 

Laser treatment for these scars is more invasive. There are two lasers used to treat them, either erbium or CO2. These lasers both emit light at wavelengths that are absorbed by water and ablate, or shave, the tissue. “They actually reduce the step-off from the scar border to the normal skin, and they promote some new collagen growth right in the area where there is a little dell [indentation] in the scar,” says Tung. Because they break the surface of the skin, “these do have some healing associated with [them].”

Non-ablative lasers can also be used on atrophic scars, although generally three to five treatments are necessary. But unlike with the ablative treatment, Tung says, “patients can go back to work, they can apply makeup right after the procedure, and carry about their normal day.”

For people who aren’t willing to undergo surgical scar revision but have a sunken scar, a dermatologist can inject a soft-tissue filler, such as collagen, to plump up the area. But collagen injections aren’t permanent and often need to be repeated.

An individual laser treatment generally costs $200 and up, depending on the size of the scar. The expense may be covered by insurance, especially if the scar has created a clear functional problem, such as preventing someone from opening the mouth fully. Both Tung and Alster say they often write letters on patients’ behalf to insurance companies.

Laser scar therapy can be done at any time, although usually after the incision has healed for six to 12 months. But “if someone is developing an abnormal scar response,” says Tung, we would like them to be referred as soon as possible so we can do something to improve that quickly.” 

Earlier and less expensive therapies include over-the-counter silicone sheeting, which may work by hydrating the wound and reducing some of the new blood vessel formation. The sheets are worn over the scar for 12 to 24 hours a day, two to four months, beginning as soon as the wound heals over.

Products like Neosporin Scar Solution start around $30. “If you can treat the scars very early on, you can notice good improvement. It minimizes the size of the scar, reduces the firmness, also causes the redness to settle down, as well as minimizes some of the itching,” Tung says. 

“You’re not going to get as profound effects with these topical therapies as you might with in-office procedures,” she says, “but definitely they’re nice adjunctive products.”

People who have a history of developing keloid or hypertrophic scars may be able to prevent abnormal scars from forming in the first place by working with a dermatologist or plastic surgeon shortly after surgery. The most common treatment is one or more steroid injections at the surgical site in conjunction with the use of silicone sheeting. Treatment length may vary, depending on whether the developing scar is hypertrophic or keloid.

Tung always advises her patients to keep checking their scars for new bumps or nodules, since some types of cancers can metastasize to the skin. “If there is something new on your skin,” she says, “we’d like to have you come in and we can look at it and see if something needs to be addressed.”

A variety of techniques can help minimize the appearance of surgical scars.

New Hope for Old Wounds

Plain old vitamin D might finally be ready for its day in the sun. New research is shedding light on the leading role that this vitamin may play in preventing cancer and in keeping tumors in check.

Vitamin D isn’t technically a vitamin, since it’s produced in the body as a result of exposure to sunlight (“vitamins” are essential to life but by definition can be obtained only outside the body, through diet or supplements). It’s only when we don’t get enough sun that our bodies don’t make enough vitamin D and we need to get it from other sources. But while one of those sources, milk, is fortified with enough vitamin D to prevent the bone disease rickets in children, dietary sources—even a multivitamin&mdash;don’t provide nearly enough D to help prevent cancer, many scientists now say.

New findings are showing that vitamin D acts as a sentinel to help regulate cell growth and prevent a cell from becoming malignant, says Boston University Medical Center researcher Michael Holick, PhD, MD. “And that’s why we think that you need an adequate vitamin D level throughout your entire life, and that [anytime] you become vitamin D-deficient, you put yourself at increased risk of potentially developing a malignancy later in life, because you’ve lost the policing ability of vitamin D to help keep cell growth in check.”

The prescription? Sensible sun exposure for your skin type, plus vitamin D supplements. The payback? Greatly reduced risk of colon, breast, prostate, and other cancers, a growing body of research is showing.

As early as the 1940s, scientists noticed that people who lived in northern states—like Vermont, New Hampshire, and Massachusetts&mdash;were more likely to die of malignancies other than skin cancer than people who lived in Texas, South Carolina, or Georgia, says Holick. The implication even then, he adds, was that “there is some immunity provided by the sun.”

But only in the last decade or so have researchers begun to zero in on vitamin D as the source of that immunity. One clue was that prostate cancer is twice as deadly among African-Americans as Caucasians in the United States; the only other place in the world with as high a death rate from that disease is Norway.

“A question you really have to ask yourself is, ‘How are African-Americans like Norwegians?’ ” says cancer biologist and epidemiologist Gary Schwartz, PhD, because they have almost the same rate of death from one of the most common cancers in the world.

Schwartz, a researcher at Wake Forest University School of Medicine, says, “They don’t look a lot alike, and they’re not genetically alike,” but it turns out that members of both groups tend to have low levels of vitamin D in their blood.

'How are African-Americans like Norwegians? They don’t look a lot alike, and they’re not genetically alike,' but it turns out that members of both groups tend to have low levels of vitamin D in their blood.

The skin pigment melanin hinders African-Americans in synthesizing vitamin D; at the same time, Norwegians—and other Scandinavians&mdash;far from the equator, have difficulty getting enough sunlight to produce adequate vitamin D. Schwartz says that in terms of vitamin D synthesis, “African-Americans are essentially Scandinavians all year round.”

He adds, “The reason that it’s potentially so interesting is that it’s something that’s completely remediable.” No one can go back and remove a past exposure to a toxin, or alter a genetic susceptibility, but people can readily change their blood levels of vitamin D.

Other studies have implicated vitamin D in incidence or survival rates for colon, breast, endometrial, and lung cancers, among others.

In a study of health professionals published last year by the 

, men with highest blood levels of vitamin D (10 nanograms per milliliter higher than those with the lowest levels) had about two-thirds the risk of dying from cancer—and even more dramatic protection from cancers of the digestive system. Other work, published last September by the American Association for Cancer Research, showed that higher intake of vitamin D was associated with a lower risk for pancreatic cancer. And rates of kidney cancer are greater at northern latitudes than among people who live near the equator, according to research published in December in the 

In a seeming paradox, multiple studies have suggested that people who get regular exposure to the sun on the job have a decreased risk of melanoma. And according to a 2005 study published in the 

, people who had the most sun exposure as a child and young adult are less likely to die of melanoma even if they do get it.

Not only does vitamin D play a role in who gets cancer, but it seems to also help keep cancers from being as aggressive.

For example, patients with higher levels of vitamin D when they first receive a diagnosis of lung cancer may survive longer. In one recent study of patients with early-stage, non-small cell lung cancer at Massachusetts General Hospital, “individuals who had higher vitamin D levels had a better prognosis even up to 10 years later,” says Edward Giovannucci, MD, ScD, a professor of epidemiology and nutrition at the Harvard School of Public Health. That study was published last November in the journal 

In other work, published last year in the journal 

, mice fed a vitamin D—deficient diet developed more aggressive, faster-growing colon tumors than did mice who had adequate vitamin D when the tumors were induced.

Some research has been less conclusive. Participants in the Women’s Health Initiative study seemed to gain no protection from taking 400 units of vitamin D a day for seven years and had about the same rates of colon cancer as women who took a placebo. But Holick says that he pointed out to the authors of the research, published early last year in 

, that women who entered the study with the lowest levels of vitamin D in their blood had about 2½ times the risk of developing colon cancer during the next eight years compared with women who had the highest blood levels.

The state of knowledge of how much vitamin D is enough to protect against cancer has changed a lot since that study began. Unfortunately, the amount of vitamin D that women in the study took was probably not enough to make an impact, says Giovannucci. “When the study was designed probably 10 years ago or so, the understanding was that 400 or even 200 units of vitamin D would be sufficient. But our understanding now is that we probably need much more vitamin D to have any influence.”

How much vitamin D? “We all need to increase our vitamin D intake,” says Holick.

“I personally, and most of my family members, now take 1,000 International Units of vitamin D3 a day. That’s what we think you need to satisfy your requirement if you’re not getting enough of it from sun exposure.”

He says he takes a supplement in that amount daily, year round, even though he plays tennis and cycles in the summertime. And when he is outside in the summer, he spends part of the time—15 minutes or so&mdash;without sunscreen.

Sunscreen blocks DNA-damaging UVB radiation, but those are the same wavelengths of light that help synthesize vitamin D. “You don’t want to get a sunburn, ever,” Holick says. “But I typically will go out, get some sun exposure, and then put sunscreen on, so I take advantage of the beneficial effect and prevent the damaging effects due to excessive exposure.” Recommendations for adequate vitamin D supplements depend somewhat on a person’s lifestyle, skin color, age, and overall health. A light-skinned lifeguard in a bathing suit on a sunny summer day probably synthesizes as much as 20,000 or 30,000 units of vitamin D, says Giovannucci. People with very dark skin probably need about 10 times as much sun exposure to synthesize the same amount of vitamin D as people with very light skin—or may need more from supplements if they aren’t getting that much sun exposure.

You don’t want to get a sunburn, ever. But I typically will go out, get some sun exposure, and then put sunscreen on, so I take advantage of the beneficial effect and prevent the damaging effects due to excessive exposure.

Recommendations for adequate vitamin D supplements depend somewhat on a person's lifestyle, skin color, age, and overall health. A light-skinned lifeguard in a bathing suit on a sunny summer day probably synthesizes as much as 20,000 or 30,000 units of vitamin D, says Giovannucci. People with very dark skin probably need aboout 10 times as much sun exposure to synthesize the same amount of vitamin D as people with very light skin—or may need more from supplements if they aren't getting that much sun exposure. 

Obese people may need more vitamin D (because the vitamin is sequestered in fat), and so do people who can’t readily absorb nutrients from their gut into their bloodstream.

Also, people need more supplementary vitamin D as they age, because their skin and kidneys gradually become less efficient at synthesizing vitamin D and converting it into its active form.

Holick recommends getting blood levels of vitamin D measured once a year, in late fall. (The amount of vitamin D you make from sunlight from spring into fall determines your stores for the year.) “If you are deficient then, you will remain so throughout the winter,” he says.

But there is still controversy about what makes for an adequate blood level. Blood tests measure not vitamin D itself, but a compound that is made from vitamin D by the liver, called 25-hydroxyvitamin D, or calcidiol. Doctors had thought that levels of 16 to 20 nanograms of 25-hydroxyvitamin D per milliliter of blood were adequate. But researchers are finding that even for bone health—and probably also for cancer prevention&mdash;levels of around 30 to 40 are optimal.

“So someone with 25, which would not be considered deficient by current standards, would do better to get his or her levels up to 30 at least,” says Giovannucci. However, “unless your physician is very up on vitamin D literature, if your values are even like 15 or 20, the lab is likely to say ‘normal’ and your physician is not going to worry about it and say your vitamin D level is fine.”

Relying on dietary sources alone probably won’t work to get your vitamin D levels high enough. “There’s essentially no vitamin D naturally occurring in our diet, and very few foods are fortified with vitamin D,” says Holick, “and it’s so little that it’s inadequate to satisfy your requirement.”

Milk or orange juice fortified with vitamin D have only about 100 International Units in a glass. And Holick has found that milk very often doesn’t have as much as it says it does on the label. Salmon contains high levels of vitamin D, perhaps as much as 1,000 units a serving, but that’s only in wild salmon, he says, and “you’d have to eat it every day.” Taking 1,000 units a day in the form of a supplement will never be too much, Holick says. Even if you get outside a lot in the summertime, the body knows how much you’re making in your skin, and it destroys any excess.

Giovannucci says the guidelines for dietary intake—200 to 600 units a day, depending on age&mdash;need to be revised, and that some people may need as much as 2,000 units a day of vitamin D to get their blood levels up to adequate amounts. Sun exposure is the most efficient way to make vitamin D, he says, although he finds it impractical to make specific recommendations. “But at the same time, I think that sometimes the messages of avoiding sun and always putting on sunscreen are too extreme.”

Cancer prevention is examined in a new light.

Diana Steele

Pinpointing Progress

New Hope for Old Wounds

The Vitamin D Difference

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