Us vs. Cancer

By Alex Daley and Doug Hornig

That sounds like a pretty gloomy forecast, doesn’t it?

It isn’t, though, not really. Because the key word in that sentence is “a.” There won’t be a cure for cancer. But there will be cures for cancers.

In common parlance, “cancer” is understood as any kind of abnormal cell proliferation over which the body fails to exert control. But this means it is haphazardly applied to over 200 different diseases with some basic similarities – cancerous cells all grow, invade, erode, and destroy surrounding normal tissue –but which have a wide variety of causes, symptoms, and appearances, and which each require distinct care and treatment.

Thus, when fighting cancer at the biological level, you have to treat nearly every cancer differently… and very carefully.

(In professional circles the preferred term for this group of disorders has become oncological diseases, but for practical purposes we’ll continue to use the more common, singular form of the noun.)

Cancer is tough to treat because of what it isn’t. There is no virus or bacterium that directly causes it. You can’t “catch it” from another person or an unclean surface or through the air. Environmental factors may play a role, but again, they are not causative. Cancer is a disease of the genes. It happens when our own bodies turn on us, when some kind of genetic malfunction allows cells to proliferate wildly, uncontrollably, and unstoppably.

Normally, our bodies are nicely equipped to keep our cells humming along. We have both growth-promoting genes, which ensure healthy cellular reproduction, and growth-suppressing genes, which keep that reproduction in check. It’s a delicate balance, though; and unfortunately, either of these can go haywire. In both cases – if growth-promoters become overly enthusiastic about their job or if growth-suppressors fail to do theirs –the result is the same: cancer.

Up to now, all treatments that kill cancer cells cause collateral damage to healthy tissues of the body. But that is poised to change.

In the long run, conquering a genetic disease means discovering a cure that works at the genetic level. We’re getting there. Decades of research are just now beginning to bear fruit, and the result will soon be a revolution in cancer therapy – a revolution that will not only save countless lives but will create incredible wealth for the scientists and companies involved and those who invest in them.

Not that we haven’t already made substantial progress. For example, 90% of breast cancer victims survive for at least five years if diagnosed after 2001, compared with only 75% as recently as 1975-77. And with prostate cancer, five-year survival has rocketed to fully 99% of those diagnosed in the past ten years, vs. 68% in the mid ’70s.

The raw number of US cancer survivors – defined as anyone who has been diagnosed with the disease but remains living – is on the rise as well. That figure was three million in 1971; it more than tripled to 9.8 million in 2001; and it further increased to 11.7 million in 2007, with seven million aged 65 or older. These numbers far outstrip demographics; the near-quadrupling of cancer survivors from 1971-2007 happened against the background of just an 80% increase in the over-65 population. The cancer diagnosis is not the all-but-automatic death sentence it once was.

These statistics are encouraging. But they’ve been achieved with medical techniques that will one day be looked back on as exceedingly crude: “slash, burn, and poison,” as detractors term the standard triumvirate of surgery, radiation, and chemotherapy.

Each of these separately or in combination carries risks and side effects that are on the serious side – ranging from highly uncomfortable through barely tolerable to outright lethal. It’d be nice to have something in the toolkit that is not as potentially hazardous as the disease itself. It would be even better if that something worked dramatically, not just incrementally, better. Until recently, such treatments have eluded us. Now though, gene-based, targeted therapies have arrived.

Slowly, we’re moving from an understanding of what composes the genetic structure – thanks to the Human Genome Project – to understanding how it works in a dynamic system. As we begin to get it, we can start looking for an answer to the question of what to do when things go wrong.

It sounds so straightforward when expressed like that. However, it’s anything but. There are tens of thousands of scientists at work worldwide seeking a cure. To find it, they’re testing hundreds of different approaches, most of which were science fiction just a few years ago. It’s a full-out sprint to the finish line, nothing spared. Not money, not time, not talent – because fame and fortune await the winners.

But there are stumbling blocks. The scene in today’s labs was pretty well summed up by the title of a recent Forbes article: Cancer‘s New Era of Promise and Chaos. “Promising” because of the amount of genetic decoding that has already been done, and the breathtaking speed at which further research is proceeding, but “chaotic” because the more we learn, the more complex the problem is revealed to be.

In a brief article such as this, it is impossible to cover all of the research being done on cancer or to provide in-depth coverage of any of them. But in general, nearly everyone is working on a targeted therapy of some kind, i.e., something that homes in on cancer cells while sparing healthy cells the damage caused by surgery, radiation, or chemo.

Our knowledge of these diseases is progressing at a remarkable rate. (If you have some technical expertise, this extensively detailed paper is a good summary of the present state of our knowledge… though, like any publication in a field moving this quickly, it becomes just a little more out of date with each passing day.) And the approaches to treating it are evolving just as quickly.

Following in no particular order are some highlights of new treatment techniques that are either already here, in human clinical trials, or just over the horizon. Some are probably stopgap measures, variants of current therapies to employ until it becomes possible to simply silence bad genetic information. None of them purports to be effective against all cancers, or even applicable to all people with the same cancer. There are undoubtedly some we’ve overlooked. And tomorrow’s headlines could well trumpet some breakthrough no one knows about yet.

Already Here

Hormone therapy. Certain natural hormones assist some cancers to grow, and in these instances the proper medication can interfere with the activity of the hormone or stop its production.

Proton therapy, one of the most promising near-term replacement possibilities for traditional radiation, directs beams of protons (instead of X-rays) at a tumor. It has a tighter beam that can be controlled in three dimensions, meaning a lot less lateral scatter than X-rays and no need to pass the beam through tissue behind the target area, thus eliminating much damage to surrounding, healthy tissue. See the Casey Research article on the subject.

Liposomal therapy takes existing chemotherapy drugs and packages them inside liposomes (synthetic fat globules). The liposome helps the drug penetrate the cancer cells more selectively and decreases possible side effects.

Biologic therapy (also called biotherapy and immunotherapy) is a catchall category of treatments that attempt to produce antitumor effects primarily through stimulation of natural host defense mechanisms or by the administration of natural or manmade immune system components.

Angiogenesis inhibitors prevent the formation of new blood vessels so that tumors cannot grow. They are well tolerated, not toxic to most healthy cells, and can be applied to cancer that is metastasizing.

Thermal High Intensity Focused Ultrasound (HIFU) uses ultrasound to raise the temperature within the target to 65° to 85°C, destroying the diseased tissue by coagulation necrosis. It’s in limited use today to treat a few primary cancers, notably prostate cancer. HIFU’s long-term effectiveness is still in question.

Radiofrequency ablation (RFA), also in general use today, involves the insertion of a thin needle, guided by computed tomography (CT) or ultrasound, through the skin and into the tumor. Electrical energy delivered through this needle heats and destroys the cancer cells.

Monoclonal antibodies (MAbs) are cloned from a unique parent. Naked monoclonal antibodies (MAbs without any drug or radioactive material attached to them) have been used to treat cancer for more than a decade by binding to specific antigens and acting either as markers for destruction by the body’s immune system or blockers of activation and continued growth of certain cancer cells. More recently, conjugated MAbs (those joined to a chemotherapy drug, radioactive particle, or cytotoxin) have come onto the scene. Seattle Genetics’ recently approved drug Adcetris is a particularly promising conjugated MAb.

In Clinical Trials

Telomerase therapy. Malignant cells continue to grow because apoptosis (cell death), the fail/safe mechanism of cellular chemistry, is turned off, and their chromosomes will not become unstable no matter how many cell divisions they undergo. The faulty action of an otherwise useful enzyme called telomerase facilitates this, giving cancer a kind of immortality. A drug which inactivates telomerase might be effective against a broad spectrum of malignancies.

Molecular targeted therapy targets molecular components within the cell-signaling pathways that support tumor survival and growth. The goal is to disrupt cell duplication (i.e., tumor growth) and promote cancer-cell death.

Reovirus (short for Respiratory Enteric Orphan virus) therapy involves five days of intravenous injections with a proprietary variant of a virus found in nature. This virus feasts on cells with a particular characteristic – the activation of the Ras pathway – which promotes growth if it’s turned on, as it is in 2/3 to 3/4 of cancer cells. Side effects are few and minimal. If all goes well, the reovirus could be marketed as early as 2012.

On the Horizon

RNAi (RNA interference) is particularly exciting because it’s true genetic medicine, applied right where cancer begins. It involves “turning off” messenger RNA that is carrying bad genetic information before that RNA can do its harm. At the moment, RNAi research has been directed primarily at other genetic abnormalities, and its potential use in cancer treatment is largely unexplored. But it will be. For a closer examination of RNAi, see the special Casey Research report Kill the Messenger.

Nanobubbles are another experimental delivery system. One technique currently being tested on animals delivers anticancer drugs in packets of nanoparticles to the tumor, where they accumulate. Ultrasound can then be directed at the target, popping the bubbles and releasing the drug within a well-defined area. A second, unrelated line of research uses antibodies to deliver a packet of gold nanoparticles to the cancer cell. An intense, focused laser beam is then used to explode the nanobubble, bursting the cell.

Mechanical High Intensity Focused Ultrasound, a second variant of HIFU, is in the early experimental stage. It delivers the ultrasound in a manner that just shakes the tumor cells, rupturing their membranes, causing them to spill their contents. The toxic spill then alerts the immune system, leading to the production of tumor-fighting white blood cells.

Hyperthermia therapy. All these treatments are highly experimental, as researchers explore a number of different ways of delivering a lethal amount of heat to the target. Among the possibilities: microwave heating, induction heating, magnetic hyperthermia, and the direct application of heat through the use of hot saline solution pumped through catheters. Tests also have been conducted with carbon nanotubes that selectively bind to cancer cells. Lasers are then used that pass harmlessly through the body but heat the nanotubes, causing the death of the diseased cells.

Way Out There

Everyone loves the idea of microscopic robots patrolling the human body in search of problems. Since they were first envisioned, these nanobots have been regarded as the potential holy grail of cancer treatments. The idea of a multitude of miniscule robots in the bloodstream armed with a multitude of payloads to combat all sorts of different diseases, happily chewing up every compromised cell before it can do any harm, is very compelling. That dream, however, remains a long way off.

However, in an interim technique presently being studied, 70-nanometer attack bots – made with two polymers and a protein that attaches to the cancerous cell’s surface – carry a piece of RNA called small-interfering RNA (siRNA), which deactivates the production of a protein essential to malignant growth, thus starving the cancer cell to death. Once its job is done, the nanoparticle breaks down into tiny pieces that are simply flushed away in the urine. This would bring all the benefits of RNAi without the complications coming to light in trials with traditional delivery mechanisms.

The Opportunity for Investors

Right now, the majority of the advanced techniques we’ve mentioned above are either in the late stages of laboratory testing, about ready to be deployed in the first few human patients, or already being studied in hundreds of cancer victims. Major pharmaceutical companies, venture capital firms, university research labs, nonprofits, and individual biotechnology entrepreneurs are pouring billions of dollars into the sector every year.

But how do you know whom to back?

Of course, there is no certain way to separate the winners from the losers ahead of time – and there will be multiple examples in both categories as this race progresses. However, it is possible to increase the likelihood of success. Here is a brief primer:

Always bear in mind that this is a high-risk/high-reward sector. Fortunes can shift in a heartbeat. Large investors line up their bets early, backing some early-stage companies more heavily than others. But unexpected results from a clinical trial can quickly topple an early favorite or give rise to a dark horse. Depending on your tolerance for risk, decide where you wish to invest along the development curve, from early-stage exploratory research to products already in the market.

Conduct your own self-education. You’ll need some basic grounding in physiology. You’ll have to acquaint yourself with what is and isn’t cutting edge tech and understand the investing implications of backing technology that could take months, years, or even a decade or more to come to market. And you’ll have to develop the ability to parse trial results. For instance, it is critical to be able to distinguish between a negative test result that is merely a temporary setback and one that means curtains for the drug candidate (and thus often the company). If you can’t do all this on your own, at least find a trustworthy guide.

Learn about the team. Within many technology silos there will be more than one company doing similar research. It’s important to understand not only the technical differences among their approaches but the value of their teams as well. Many of the best technologies fail to reach the market simply because of bad management – nowhere is that the case more often than in biotechnology, where companies must manage massive research spending and plan for huge cost contingencies, often for years before seeing revenue. You’ll want to learn the ins and outs of the approval process and the costs associated with each step to assure yourself that management is spending wisely and you won’t be diluted too badly in the event a contingency plan has to go into effect.

Develop a confident trigger finger. Once you have figured out what technologies are the best bets for your investing dollars, you must be able to pull the buy/sell trigger on a given investment dispassionately and without hesitation. In order to generate the really big returns, you must be invested ahead of the crowd, before the potential payoff is already baked into the share price. And you must be quick to sell when the moment is right.

Don‘t jump in too early. Retail investors should usually look for are companies that have produced some promising results in real-world tests, but are still short of Phase III success (typically the last major stage before commercialization), the point at which the “limited risk” crowd will be rushing to board the train. Those are the people, mostly larger investors, who either have reluctance to, or are specifically prohibited from, taking too much of a chance, and who instead seek “safe” 10% or 20% gains. Buy in before they get there. It’s to them that you, as a mid-stage investor, will sell your stock.

Check the pipeline. You usually want to select companies that are more than one-trick ponies. Any company staking everything on a single drug candidate is a very risky investment. One strike and they are out. There are times when the potential payoff is enticing enough to make these investments worthwhile, but far more preferable are companies that have a handful of therapies in the testing pipeline… or better still, ones that have developed a unique platform from which they can launch multiple products.

Check the pipeline again. At the same time, watch that your company is not spread too thin. Obsession with the pipeline at the expense of getting drugs to market in a reasonable timeframe can easily lead to running out of cash, a potentially deadly event that has taken down many a biotechnology company.

Hedge your bets. In a field as complicated and diverse as cancer research, you really have no choice. If you stock your portfolio with several companies, all of them pursuing different experimental lines, you greatly enhance your likelihood of success.

The same of course is true for cancer. The more treatments there are available, the more likely it is that patients can beat the diseases. So, while there may not be a cure for cancer, there will be many. And with the right strategy, they very well might help your portfolio heal a bit too.

[The Casey Extraordinary Technology biotech portfolio features later-stage, cancer-centric companies involved with RNAi, monoclonal antibodies, and molecular targeting. Learn more about our cancer fighting portfolio.]

Bits and Bytes

First 3D Chip (PhysOrg)

To date, all computers have been built upon a two-dimensional model. Increases in power have depended on increasing the number of circuits that can be crammed on the single plane that is the surface of a chip. It’s worked well so far, but there are obviously physical limitations to how small you can shrink those circuits. Even linking chips side by side doesn’t increase efficiency much. The next generation may therefore have to reach in a different direction – into the third dimension. That is, why not create chipstacks that are connected so that electrical impulses can flow up and down as well as across the chip? Though it sounds simple, there are a lot of technical hurdles that have flummoxed researchers for many years. The problems may now have been resolved, however, due to this breakthrough joint effort announced a month ago by IBM and Micron Technologies. The day of 3D chips is dawning.

Smallest 3D Printer (TEDxVienna)

And while we’re on the subject of 3D, subscribers to Casey Extraordinary Technology already know how bullish we are on the burgeoning field of additive manufacturing, or 3D printing. These machines are rapidly getting better, cheaper, and more versatile. They’re also getting smaller, as you can see.

Does Google Want It All? (The Week)

Well, the search-engine giant is coming hard after the browser market. It’s not likely to catch Internet Explorer (IE) anytime soon, since that’s the default on Windows-based computers and most users don’t bother with anything else. Among those who do want something different, the most appealing alternative has for a long time been Mozilla’s Firefox. No longer. Google’s Chrome raced past Firefox in market share for the first time in November. Many have now pronounced Firefox a dead man walking. Is IE next?

Chrome has been a smashing success, and Android has been torching the mobile market. Next up in Google’s gunsights: the almighty iPad. The company goes to war with Apple again early this year, as it launches its first tablet at about the same time as the arrival of iPad3. It’s a risk for Google, but that’s never been a deterrent… not when you want it all.

Nano Goes Big (Technology Review)

Carbon nanotubes, one of the wonders of nanotechnology, are just a few billionths of a meter wide, and they’re among the strongest and most conductive materials known. Scaling them up to make functional products is a challenge, but some cutting-edge companies are already deeply involved. Most people have probably never heard of nanotubes. That will change, and soon.