This article first appeared in the St. Louis Beacon, Jan. 28, 2009 - I learned this week, sadly, that a lovely lady I know has been diagnosed with lung cancer. Until recently this would have been a death sentence, and still may be, but she has a far better hope of a future today because of potential cancer therapies being developed on many fronts.
Some of these new therapies act to prevent the start of cancer within cells. Others act outside cancer cells, preventing tumors from growing and spreading. The illustration indicates the seven key stages of the cancer process targeted areas for the development of cancer treatments.
Preventing the Start of Cancer
Many promising cancer therapies act within potential cancer cells, focusing on different stages of the cell's "Shall I divide?" decision-making process.
1. Receiving the Signal to Divide. The first step in the decision process is receiving a "divide" signal, usually a small protein called a growth factor released from a neighboring cell. The growth factor is received by a protein receptor on the cell surface. Like banging on a door, its arrival signals that it's time to divide. Mutations that increase the number of receptors on the cell surface amplify the division signal and so lead to cancer. Over 20 percent of breast cancer tumors prove to overproduce a protein called HER2 associated with the receptor for epidermal growth factor (EGF).
Therapies directed at this stage of the decision process use the human immune system to attack cancer cells. Special protein molecules called monoclonal antibodies, created by genetic engineering, are the therapeutic agents. These monoclonal antibodies are designed to seek out and stick to HER2. Like waving a red flag, the presence of the monoclonal antibody calls down attack by the immune system on the HER2 cell. Because breast cancer cells overproduce HER2, they are killed preferentially. The biotechnology research company Genentech's recently approved monoclonal antibody, called herceptin, has given promising results in clinical tests.
Up to 70 percent of colon, prostate, lung and head/neck cancers have excess copies of a related receptor, epidermal growth factor 1 (HER1). The monoclonal antibody C225, directed against HER1, has succeeded in shrinking 22 percent of advanced, previously incurable colon cancers in early clinical trials. Apparently blocking HER1 interferes with the ability of tumor cells to recover from chemotherapy or radiation.
2. Passing the Signal via a Relay Switch. The second step in the decision process is the passage of the signal into the cell's interior, the cytoplasm. This is carried out in normal cells by a protein called Ras that acts as a relay switch. When growth factor binds to a receptor like EGF, the adjacent Ras protein acts like it has been "goosed," contorting into a new shape. This new shape is chemically active and initiates a chain of reactions that passes the "divide" signal inward toward the nucleus. Mutated forms of the Ras protein behave like a relay switch stuck in the "ON" position, continually instructing the cell to divide when it should not. Thirty percent of all cancers have a mutant form of Ras. So far, no effective therapies have been developed targeting this step.
3. Amplifying the Signal. The third step in the decision process is the amplification of the signal within the cytoplasm. Just as a TV signal needs to be amplified to be received at a distance, so a "divide" signal must be amplified if it is to reach the nucleus at the interior of the cell, a very long journey at a molecular scale. To get a signal all the way into the nucleus, the cell employs a sort of pony express. The "ponies" are enzymes called tyrosine kinases. These enzymes add phosphate groups to proteins, but only at a particular amino acid, tyrosine. No other enzymes in the cell do this, so the tyrosine kinases form an elite core of signal carriers not confused by the myriad other molecular activities going on around them.
Cells use an ingenious trick to amplify the signal as it moves toward the nucleus. Ras, when "ON," activates the initial protein kinase. This protein kinase activates other protein kinases that in their turn activate still others. The trick is that once a protein kinase enzyme is activated, it goes to work like a demon, activating hoards of others every second! And each and every one it activates behaves the same way, activating still more, in a cascade of ever-widening effect. At each stage of the relay, the signal is amplified a thousandfold.
Mutations stimulating any of the protein kinases can dangerously increase the already amplified signal and lead to cancer. Some 15 of the cell's 32 internal tyrosine kinases have been implicated in cancer. Five percent of all cancers, for example, have a mutant hyperactive form of the protein kinase Src. The trouble begins when a mutation causes one of the tyrosine kinases to become locked into the "ON" position, sort of like a stuck doorbell that keeps ringing and ringing.
To cure the cancer, you have to find a way to shut the bell off. Each of the signal carriers presents a different problem, as you must quiet it without knocking out all the other signal pathways the cell needs. The cancer therapy drug Gleevec, a monoclonal antibody, has just the right shape to fit into a groove on the surface of the tyrosine kinase called "abl." Mutations locking abl "ON" are responsible for chronic myelogenous leukemia, a lethal form of white blood cell cancer. Gleevec totally disables abl. In clinical trials, blood counts revert to normal in more than 90 percent of cases.
4. Releasing the Brake. The fourth step in the decision process is the removal of the "brake" the cell uses to restrain cell division. In healthy cells, this brake, a tumor-suppressor protein called Rb, blocks the activity of a protein called E2F. When free, E2F enables the cell to copy its DNA. Normal cell division is triggered to begin when Rb is inhibited, unleashing E2F. Mutations that destroy Rb release E2F from its control completely, leading to ceaseless cell division. Forty percent of all cancers have a defective form of Rb.
Therapies directed at this stage of the decision process are only now being attempted. They focus on drugs able to inhibit E2F, which should halt the growth of tumors arising from inactive Rb. Experiments in mice in which the E2F genes have been destroyed provide a model system to study such drugs, which are being actively investigated.
5. Checking That Everything Is Ready. The fifth step in the decision process is the mechanism used by the cell to ensure that its DNA is undamaged and ready to divide. This job is carried out in healthy cells by the tumor-suppressor protein p53, which inspects the integrity of the DNA.
When it detects damaged or foreign DNA, p53 stops cell division and activates the cell's DNA repair systems. If the damage doesn't get repaired in a reasonable time, p53 pulls the plug, triggering events that kill the cell. In this way, mutations such as those that cause cancer are either repaired or the cells containing them eliminated. If p53 is itself destroyed by mutation, future damage accumulates unrepaired. Among this damage are mutations that lead to cancer. Fifty percent of all cancers have a disabled p53. Fully 70 percent to 80 percent of lung cancers have a mutant inactive p53 -- the chemical benzo[a]pyrene in cigarette smoke is a potent mutagen of p53.
6. Stepping on the Gas. Cell division starts with replication of the DNA. In healthy cells, another tumor suppressor "keeps the gas tank nearly empty" for the DNA replication process by inhibiting production of an enzyme called telomerase. Without this enzyme, a cell's chromosomes lose material from their tips, called telomeres. Every time a chromosome is copied, more tip material is lost. After about 30 divisions, so much is lost that copying is no longer possible. Cells in the tissues of an adult human have typically undergone 25 or more divisions. Cancer can't get very far with only the five remaining cell divisions, so inhibiting telomerase is a very effective natural brake on the cancer process and is #6 in the figure. It is thought that almost all cancers involve a mutation that destroys the telomerase inhibitor, releasing this brake and making cancer possible. It should be possible to block cancer by reapplying this inhibition. Cancer therapies that inhibit telomerase are just beginning clinical trials.
Preventing the Spread of Cancer
7. Stopping Tumor Growth. Once a cell begins cancerous growth, it forms an expanding tumor. As the tumor grows ever-larger, it requires an increasing supply of food and nutrients, obtained from the body's blood supply. To facilitate this necessary grocery shopping, tumors leak out substances into the surrounding tissues that encourage the formation of small blood vessels, a process called angiogenesis. Chemicals that inhibit this process are called angiogenesis inhibitors. Two such natural angiogenesis inhibitors, angiostatin and endostatin, caused tumors to regress to microscopic size in mice, but initial human trials have so far been disappointing.
Laboratory drugs are more promising. A monoclonal antibody drug called Avastin, targeted against a blood vessel growth promoting substance called vascular endothelial growth factor (VEGF), destroys the ability of VEGF to carry out its blood-vessel-forming job. Given to hundreds of advanced colon cancer patients in 2003 as part of a large clinical trial, Avastin improved colon cancer patients' chance of survival by 50 percent over chemotherapy.
Even more promising are vaccines directed against tumor cells. A lung cancer vaccine now being tested at the Siteman Cancer Center stimulates the immune system to destroy cells carrying on their surface a protein called MAGE-A3. This protein isn't found on any of the cells of healthy people, but is common on cancer cells - for example, half of the people with the most common type of lung cancer ("non-small cell lung cancer") have it on their lung cancer cells. Doctors are using the MAGE-A3 vaccine for patients who have undergone treatment for lung cancer but are at high risk of recurrence. The study involves more than 400 hospitals in 33 countries and will enroll over 2,200 patients who have undergone complete surgical removal of a stage I, II or IIIa MAGE-3A-positive non-small cell lung cancer tumor within six weeks. Preliminary results in smaller trials indicate that the vaccine markedly improves chances of survival. This test will give a definitive answer.
'On science'
George B. Johnson's "On Science" column looks at scientific issues and explains them in an accessible manner.
Johnson, Ph.D., professor emeritus of Biology at Washington University, has taught biology and genetics to undergraduates for more than 30 years. Also professor of genetics at Washington University’s School of Medicine, Johnson is a student of population genetics and evolution, renowned for his pioneering studies of genetic variability.
He has authored more than 50 scientific publications and seven texts.
As the founding director of The Living World, the education center at the St Louis Zoo, from 1987 to 1990, he was responsible for developing innovative high-tech exhibits and new educational programs.
Copyright George Johnson