Nearly everyone has heard of the War on Cancer, which was launched during the Nixon administration with the passage of the National Cancer Act of 1971. The goal of this legislation was to eradicate (or at least significantly decrease) the number of U.S. cancer deaths. Progress in meeting this goal has been slow over the past 40 years. Sadly, we lose more of our citizens to cancer every two years (an estimated 1.14 million) than the total number of military casualties suffered by our troops in the entire history of our country (about 850,000 men and women). Like many wars, this one turned out to be much tougher to win than many people thought it would when the NCA was set into law.
Advances in molecular biology, biotechnology, and genomic sequencing have contributed significantly to the discovery of the molecular cause of a wide variety of cancers in recent years. Multiple DNA analyses have shown that cells within the tumor mass generally contain a large number (tens to hundreds) of different mutations. The changes seen in one cell are often distinct from those observed in distant cells, making each individual tumor that much more difficult to treat. Despite this heterogeneity, genomic sequencing of different cancer types has also revealed that individual tumors share an attribute of snowflakes: while they are all uniquely different, they also share some similar features. Common mutations have been found across many different types of cancer. This suggests that drugs that were originally designed to treat just one specific type of cancer might work on different tumor types as well. This idea is being tested in a number of clinical trials as part of a precision medicine approach to treating cancer.
Despite these developments, many people don’t have a good understanding of how drugs that fight cancer work, and what their limitations are. A recent article in the New England Journal of Medicine reported that a majority of late stage colon and lung cancer patients didn’t understand that the chemotherapy used to treat their disease would likely not cure them. Clinical cancer trials are not designed to be treatments per se (which is why they often have placebo or “current standard of care” control groups) but to gather information that may be helpful down the line for the treatment of others. The approaches taken by many anti-cancer treatments actually have strong parallels to a variety of classic military strategies. Comparing these different tactics side by side (and in a simplified way) may help illuminate how these cancer therapies are designed to work.
Aerial Bombardment and Artillery Fire = Surgery
If a small number of enemy troops invade your territory, it may be possible to wipe them out with aerial bombs or artillery fire if they’re concentrated in a small area. To be most effective, you need to make sure that all of their troops are killed. If a few escape, they can spread to other areas where they can cause problems in the future. If the escaped troops have spread out sufficiently, then it may be impossible to eliminate them entirely.
Surgery is an effective way to remove tumors when they are still small, have not metastasized to distant sites, and are in a part of the body where they can be readily accessed. Unfortunately, many tumors at the time of diagnosis have already spread throughout the body or are inaccessible, meaning surgery won’t cure these patients.
Poison Gas Attacks = Chemotherapy (and Radiation)
Picture the bleak, cratered landscape of a muddy World War I battlefield, with both sides huddled down in their respective trenches. The German artillery launches shells containing mustard gas in the direction of Allied troops. This poison’s been designed to kill or disable large numbers of soldiers, but once it’s released, it can’t discriminate between French and German troops. Though targeted at the enemy, the gas can inflict serious collateral damage on the attacking troops if the wind blows in the wrong direction. It’s major failing as a weapon: it can’t distinguish friend from foe.
Many chemotherapy drugs act in this same indiscriminate way, and some of them, the nitrogen mustards, are chemically related to the poison gasses used in the trenches. These drugs (e.g. Melphalan) kill actively dividing cancer cells by cross-linking their DNA strands. However, their effects are non-specific. They will indiscriminately kill off many other types of actively dividing cells, such as those in your hair follicles or that line your intestines. These therapies can’t be given at too high a dose or they will kill the patient. Radiation therapy works in a similar manner to chemotherapy in the sense that it also damages DNA and it is not possible to only target cancer cells with it. Radiation can sometimes be focused on a limited treatment area, but it can’t distinguish between normal and cancer cells.
Slow The Enemy’s Advance = Enzyme Inhibitors
Visualize an enemy army that has invaded your country, and their troops are marching onward, spreading death and destruction in their wake. You want to kill the invaders, but your armories have been depleted of their most effective weapons. In this situation, slowing down the advance of your enemy can be an effective strategy while your factories work overtime to rebuild your munitions or develop new and effective weapons.
Anti-cancer drugs that function as enzyme inhibitors (e.g. imatinib mesylate (Gleevec)) work in this way. They kill (or at least slow the growth) of your cancer cells by inhibiting the activity of enzymes that play an important role in cell growth. Unfortunately, they also put selective pressure on the population of cancer cells that, as a result of chance genetic mutations, have a slightly different form of the enzyme. These cancer cells may become resistant to the original drug and multiply. If you’re fortunate these mutated cells may still be susceptible to other drugs that function in a slightly different way.
Navy Seal Teams = Monoclonal Antibodies
Think about a trained platoon of Navy Seals whose mission is to kill foreign troops that have occupied a city. They are trained to recognize enemy soldiers by watching out for distinctive features of the enemy, such as their speaking a unique language. The highly trained Seals will initially do a good job of picking off the enemy troops and significantly reduce their numbers. However, the enemy soldiers will eventually spread the word among their remaining troops to stop speaking their native language. Their numbers will then increase because they can now evade your ability to identify and kill them. Unfortunately, there will also be some civilians who are not enemy soldiers who will be killed because, by chance, they happen to speak that same unique language. Despite the initial success of the Seals, they will need to change their strategies over time so that they can recognize the enemy by some other characteristic.
This analogy basically describes how monoclonal antibodies (e.g. rituximab (Rituxan)) kill off tumor cells. These antibodies recognize molecules on the cell surface that, in an ideal world, would only be found on cancer cells. Unfortunately, these same proteins are sometimes found on normal cells, and the antibodies attack them as well. Unlike chemotherapy, which is non-specifically toxic to both normal and cancer cells, the approach here is to focus the attack primarily on the cancer cells. These targeted antibodies won’t kill some cancer cells because they either don’t have the molecule that the antibody is looking for on their cell surface, or the cells have developed a resistance to the drug via some other mechanism. These surviving cancer cells may then replicate to regrow the tumor, which may (or may not) be susceptible to other drugs.
Smart Bombs = Antibody-Drug Conjugates
This approach is similar to the situation described above where the Seals are engaging an infiltrating army of enemy soldiers. In this situation, however, the Seals are much better armed: they carry hand grenades that they can use to kill the enemy. This makes them much more effective than their fellow fighters that lack these weapons. As before, enemy soldiers that can’t be recognized can’t be killed.
Antibody-drug conjugates (e.g. brentuximab vedotin (Adcetris)) use monoclonal antibodies to deliver a payload of highly toxic molecules to cells to which the antibody binds via a specific cell surface molecule. Two things are needed for this therapy to be effective: the targeted molecule should be found only (or mostly) on the cancer cells, and the toxic molecule should not be released until it is inside the targeted cell. These toxic molecules are so poisonous that only a few molecules are needed to kill a cell. Cancer cells lacking the appropriate cell surface molecule (or which have it, but can’t internalize the lethal payload) will resist this line of attack.
Siege Warfare and Naval Blockades = Angiogenesis Inhibitors
Picture a medieval castle under attack, surrounded by an army that prevents food (and other supplies) from reaching those living inside the ramparts. Starving your enemies can be an effective approach to killing them off, or at the very least, preventing them from spreading. Naval blockades do the same thing if they can successfully prevent an enemy from being resupplied, as was done against the South during the Civil War.
Cancer drugs known as angiogenesis inhibitors (e.g. bevacizumab (Avastin)) employ this concept as a therapeutic approach. They block the development of blood vessels within growing tumors, which in turn reduces the flow of nutrients in the bloodstream to the cancer cells. These treatments are better at slowing down the growth of tumors than eliminating them.
Recruitment of Resistance Fighters = Immunotherapy
Imagine being able to train the local populace to recognize, attack, and kill invading enemy soldiers they encounter in every city, village, and house. This would be an ideal way to deal with an occupying army, but there are two challenges here. The first is developing an effective training procedure so that the fighters are skilled enough to achieve their mission, and the second is being able to recruit a sufficiently large number of these home-grown fighters to fully engage the enemy.
This is the concept that immunotherapy approaches (e.g. ipilimumab (Yervoy)) bring to the cancer battle. The idea is to train the immune system to recognize and destroy cancer cells wherever they are hiding in the body. There are many technical challenges with this approach, but the essential problem can be simply stated: the correct cells must be recognized and eliminated, and you cannot mis-identify normal cells and kill them as well.
Deny Access by Blowing Up the Bridges = Viral Vaccination
One effective approach to protecting the homeland is to prevent foreign troops from invading in the first place. Set up a defensive system so that the invaders cannot establish a beachhead on your terrain, and you won’t need to fight them in the streets later on. One way to do this is to dynamite the bridges and tunnels that could be used to access your territory.
This is the basic idea behind immunizing young women (and men) against human papilloma viruses (e.g. Human Papillomavirus Quadrivalent Vaccine (Types 6, 11, 16, and 18) Vaccine, Recombinant (Gardasil)). Infection by certain strains of papilloma virus can eventually lead to cervical cancer in women and other types of cancer in men. People who are successfully immunized are resistant to the viruses and won’t develop these cancers later on. Unfortunately, there are very few cancers whose growth is thought to be initiated by viral infections. As a result, this approach wouldn’t work against a large number of different tumor types.
Assassinate Enemy Leaders = Kill Cancer Stem Cells
If you can kill the leaders of the enemy army, you will seriously weaken it and will have a much easier time fighting the remaining troops. The primary goal here is to find, identify, and extirpate these top commanders, who are often hidden away and difficult to locate. They also have been known to employ doppelgangers to draw attention away from the real individuals, further complicating the task of finding them.
There is a parallel to this strategy in cancer therapy: try to eliminate cancer stem cells. These cells are posited to be the source of all of the other cancer cells, and it is believed that eliminating these rare cells might be a successful treatment strategy. As with some of the other approaches described above, the challenge is to identify and destroy these cells without wiping out a significant number of normal cells. While there are no medicines currently on the market using this approach, some companies (e.g. Verastem) are focusing on this drug development strategy.
Blitzkrieg = Combination Therapy
This is an all out attack on the enemy in which you attempt to overwhelm it by using a massive display of force in a short time period. In many of the scenarios I have described above, the enemy’s strategy evolves in response to the attack so that it is no longer effective. If you want to avoid the development of a resistance movement, or block your enemy from re-arming, a blitzkrieg attack might do the trick.
Combination treatments (e.g. folinic acid/fluorouracil/irinotecan/oxaliplatin (Folfirinox)) are the blitzkrieg approach in cancer therapy. Employing multiple drugs at the same time to kill off tumor cells can be effective at achieving remissions, or at least slowing down the growth of the cancer. One major problem with this approach is that the toxicities associated with each individual drug in the mixture may not just be additive, they may also be synergistic and cumulative. Killing the patient along with the tumor is not an effective cancer treatment strategy, so dosing must be carefully monitored, and these drug combos can usually be administered for only a limited time.
Throw the Kitchen Sink at the Enemy = Repurposing Old Drugs for New Diseases
Sometimes your armed forces run out of options. There are no more rockets in the armory, the Air Force has dropped all of their bombs, and the Marines are out of mortars. This is when you just have to wing it and look for anything that can be used as a weapon against the enemy soldiers. Bring the muskets, the bayonets, the swords, and the crossbows to your battle. Old weapons can sometimes be quite effective if given the chance, especially when you are in desperate straits and have nothing to lose.
This repurposing approach has been employed successfully by screening drugs that were previously used in other diseases, but which had not been previously shown to work against cancer cells. The best-known example is thalidomide (Thalomid). It was originally prescribed back in the 1950’s as a sedative and as an anti-nausea agent for pregnant women, but was abandoned in the early 1960s when it was discovered to cause serious birth defects. Years later, however, it was shown to be useful in treating leprosy, and more recently thalidomide (and it’s derivatives) were found to be quite effective in treating multiple myeloma, a cancer of plasma cells.
M.A.S.H. = Palliative Agents
Sometimes the best offense is a good defense. Your troops need effective healthcare to treat their wounds and diseases acquired during battle so that they can get back to the theater of combat quickly. Having a superbly outfitted mobile army surgical hospital located near the front lines may save many lives and help wounded soldier’s return to the fight once they have recovered.
Some drugs that are given to cancer patients are not designed to attack the cancer at all. They are palliative agents and are designed to help replenish some cell type that is being damaged by the disease itself or the treatments. Examples include agents (e.g. filgrastim (Neupogen)) that stimulate the proliferation of white blood cells that are killed off collaterally by chemotherapy. This improves outcomes and the patient’s quality of life by helping them fight off potentially lethal infections while they recover from treatment.
Summary: We’re Made Advances, But We’re Not Winning the War Yet
Continued investments in basic as well as applied research will translate into new medicines and treatments that are beyond today’s science, so our commitment to funding this work must be maintained. It’s not clear that many new approaches are really needed to win the war on cancer. A stronger and more focused armamentarium using some of the cutting edge approaches I’ve defined above should significantly decrease our national losses in this battle. I’ve focused here on defining the medical aspects of our battle with cancer, but this won’t happen in a vacuum. New drugs and treatment modalities (especially combination cancer therapies) are going to be ultra-expensive, and we need to find a way to effectively pay for and deliver them. Patients will need to be coaxed into signing up for appropriate clinical trials. They will also need the help of their loved ones and employers to find the time to get treated, as well as assistance while they recover from what are often difficult-to-tolerate therapies. As with any war, the battles are never easy, but the costs of not winning are unimaginable. We must fight on.