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Searching for New Ways to Treat Lung Cancer

As I get older, cancer kills more and more of my friends and family. Lung cancer is my particular nemesis.  My brother died of lung cancer a few years ago, my closest college friend last year.  Unlike breast cancer, which we cannot prevent because we do not know its cause (and the government continues to fail to fund a serious search to find it), it is easy to prevent lung cancer.  Don’t smoke.  That’s all there is to it.  If cigarettes and tobacco were illegal, lung cancer as a common disease would disappear.

Unfortunately, our government and society condones smoking and continues to allow the tobacco industry to addict us and our children to nicotine. Americans continue to smoke, and lung cancer to kill. As someone who smoked a lot in my twenties, I feel the shadow of lung cancer more acutely as I grow older -- my younger self has put my current self at particular risk.

So it is with considerable interest that I note two recent developments in the treatment of lung cancer.  Unfortunately, neither of them offer a cure.  It is still true that if you contract lung cancer, you are quite likely to die of it, and quickly. Some 215,000 men and women were diagnosed with lung cancer in the United States in 2008, and because the five-year survival rate for lung cancer is only about 10 percent, fully 193,000 of them are expected to be dead by 2013.  

What the two new approaches do offer is hope of extending the survival rate, of increasing the number of those who escape a death sentence when diagnosed with lung cancer. By finding ways to differentiate cancer cells from normal body cells, the new approaches offer a good chance of improving the effectiveness of cancer treatment, the sort of incremental progress that is the hallmark of the war on cancer. Both new approaches are very much works in progress, neither yet a sure bet. Every year, though, with progress like these approaches represent, treatments gets a little better, survival a little more likely.

The first of the two “cancer ID” approaches involves a novel way to kill residual lung cancer cells in patients after the primary lung cancer has been surgically removed.  A major study involving more than 2000 patients at 400 cancer centers in 33 countries, a component of the study is being carried out at the Saint Louis’s Siteman Cancer Center by a group headed by Bryan Meyers, Professor of Surgery at the Washington University School of Medicine.

What makes the approach exciting is its simplicity. Most cases of lung cancer are of a type called non-small cell, and up to 50 percent of these lung cancer cells carry on their surfaces a protein called MAGE-A3 that is not present in normal tissue.  In effect, these calls are wearing a great big target that says “SHOOT ME” to the body’s immune system.  All that is required is to find a way to get the patient’s body to pull the trigger.

The trial of this therapeutic MAGE-A3 cancer vaccine is limited to less advanced lung cancer patients who have undergone complete surgical removal of the tumor within six weeks, and who are among the lucky 50 percent whose cancers carry the MAGE-A3 antigen (these sort of cell surface marker proteins are called “antigens” because the body’s immune system responds to their presence by attacking them).  The treatment is simplicity itself: patients are injected with compounds that cause inflammation to activate the immune system (pulling the trigger, if you will) and also with MAGE-A3 antigen particles (identifying the target).  If all goes as planned, the patient’s immune system will activate its killer T-cell weapon system, targeting any cells with the MAGE-A3 antigen on their surface. As only cancer cells have the antigen, only cancer cells are targeted in the wave of cell killing that follows.  Any lung cancer cells that avoided removal during surgery have a good chance of being found and killed under this immune system assault.

Success of this approach is by no means assured.  Therapeutic cancer vaccines have been tried in the past with little success. A phase 3 clinical trial of a melanoma vaccine with 1,600 patients worldwide was halted in 2006 when survival rates were no different in control groups not receiving the vaccine.

New studies offer hope of better results.  At the annual meeting of the American Society of Clinical Oncology (that is, cancer doctors) held last week, researchers reported promising but limited results for two new vaccines targeted at particular cancers. A vaccine directed at follicular lymphoma delayed remission after chemotherapy by more than one year. A new version of melanoma vaccine caused tumors to shrink in twice as many patients as those receiving standard therapy.

The point is, lots of good ideas don’t work out in practice. But preliminary small MAGE-A3 trials were encouraging (there wouldn’t have been a big follow-up study if they weren’t), and the sheer size of this study promises a pretty definitive answer as to the effectiveness of the approach. Sure looks like a good bet.

The second of the two new “cancer ID” approaches involves a key problem in chemotherapy: getting chemicals into cancer cells without poisoning other body cells.  In most chemotherapy treatments today, normal body cells are poisoned by chemicals targeted at cancer cells. It is for this reason that chemotherapy often has such a devastating effect: Unable to tell the difference between normal and cancer cells, the treatment is forced to accept the death of normal cells as the price of killing cancerous ones.

It doesn’t take a rocket scientist to see the problem here.  For the same reason that directed mailing (sending ads only to people known to be interested in the product you are selling) is more successful than mass mailing (sending ads to everybody able to receive one), so sending deadly chemicals directly to cancer cells is more successful than exposing all cells to them. 

The solution?  We need a way to package the chemical in a letter, and to address the envelope.

The approach developed by researchers in Australia is exciting in its simplicity. Like the lung cancer treatment described above, the method takes advantage of the fact that cancer cells have proteins on their surfaces that can be used to ID them. In this case the researchers have focused on the fact that 80% of solid cancer tumors have their surfaces coated with a special protein receptor, one for an important cellular signal called epidermal growth factor (egf). Most cells tend to have a few of these egf proteins on their surface, but tumor cells have vastly greater numbers of them, their surfaces studded with them like grains on sandpaper.

To take advantage of this, the Australian researchers first had to devise a suitable envelope for their chemotherapy “message.”  Taking a chance (in science, that is how progress is made, although peer-reviewed funding in the U.S. rarely rewards such aggressive research), the Australians tried an envelope-making approach that had long been written off as unlikely to work. 

Here is what they did:

1.  Preparing envelopes.  The researchers first grew cultures of a mutant bacteria whose cells are particularly sloppy in cell division, the cells pinching off small bubbles of cell membrane whenever they divide.  The researchers then used a centrifuge to harvesting large quantities of these bubbles, called minicells, from the culture.  The minicells became their envelopes.

2.  Filling the envelopes.  Using standard procedures, the researchers then loaded the minicells with chemicals, both anticancer toxins and chemicals that turn off genes that make tumors resistant to toxins.

3.  Addressing the envelopes. Finally, the researchers coated the loaded minicells with antibodies directed toward the egf surface protein.  This will cause the minicell to attach to cells with egf receptors on their surface.

The loaded and egf-addressed minicells are then administered to cancer patients. Traveling through the blood stream to tumors, the minicells bind to any egf receptors they encounter. Because cancer cells have so many more egf proteins on their surfaces than normal body cells do, many more of the loaded minicells end up bound to cancer cells than to normal cells. Responding to the binding, tumor cells engulf and destroy the minicells, and in so doing gobble up the toxic cargo the minicells carry. The result?  Tumor death, and, hopefully, patient recovery.

This approach seems to work very well in animal trials. In work reported last week in Nature Biotechnology, mice with highly aggressive uterine tumors were treated in this way. All of the treated animals were free of tumor cells after 70 days of treatment, while all the untreated mice were dead.  The researchers have conducted extensive safety tests with monkeys, and will start safety trials in humans (the first stage of clinical trials) in three Melbourne hospitals this month. 

There are no guarantees that either of these approaches will work with human patients, but both represent exciting possibilities. 

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