A ‘silver bullet’ for cancer

The really good news is that, at long last, scientists may be on their way to finding a cure for all forms of the disease.

By SHLOMO MAITAL
The Sarah Wetsman Hospital Tower (photo credit: Courtesy)
The Sarah Wetsman Hospital Tower
(photo credit: Courtesy)
How close are we to finding a cure for cancer? Some 40 years after US President Richard Nixon declared war on the disease in his State of the Union address, and following the investment of an estimated $3 trillion in research and treatment in the United States alone, there is both bad news and good news.
First, the bad: Cancer remains the biggest killer in Israel, with the disease responsible for around 10,000 of the country’s approximate 40,000 annual deaths – a ratio of one in four, and 60 percent more than those caused by heart disease. According to the World Health Organization, some 12.7 million people worldwide are diagnosed with cancer every year, and over 7 million die from it, with almost half – or 3.4 million cancer deaths – the result of smoking Cancer deaths have been on the rise in Israel since 2000, mainly due to lifestyle (e.g., smoking, obesity and alcohol consumption) and population aging. According to the Israel Cancer Association, some 60 percent of current cancer deaths can be prevented by lifestyle changes, early diagnoses and proven medical interventions. People die because they smoke and fail to get to doctors early enough.
Now, the good: More and more people are surviving cancer. A 2009 Health Ministry report shows that Israel boasts one of the highest cancer survival rates in the West, with 61 percent of males surviving the disease after a five-year recovery period, and around 67 percent of females. One reason for this profemale differential is the high and rising survival rates for breast cancer, about 90 percent – up from only 80.5 percent in 2002. New medicines, national awareness, early detection and new technologies are the overall reasons for improved cancer survival. A family physician I spoke with attributes the overall high survival rates to Israel’s excellent public health system and national health insurance.
I have a deep personal interest in cancer.
In 2001, I was diagnosed with prostate cancer.
Surgery put me among the fortunate 61 percent of male survivors. It was a close call; a few more weeks and my aggressive tumor would have spread beyond the prostate and eventually ended my life.
But the really good news is that at long last, scientists may be on their way to finding a so-called “silver bullet” – a cure for all cancers. Here is how.
While there are more than 120 different types of cancer, treatments thus far have been highly specific to individual types of the disease. For instance, a drug called Taxol, produced from the bark of the Pacific yew tree, treats breast cancer. But is there a drug or therapy that will successfully treat all types of cancer? On September 15, 2008, I described in The Jerusalem Report a n ew a pproach t o curing cancer, invented by Prof. Yoram Palti of the Technion-Israel Institute of Technology, which “explodes” cancer cells when they divide, by placing an electromagnetic field around the affected area in the body.
When the walls of a cancer cell grow thin as it divides, the electromagnetic field ruptures them and kills the cell. Palti’s start-up, Novocure, has since successfully passed clinical trials for its device to deal with hard-to-treat brain tumors and lung cancer.
Another hoped-for silver bullet was the discovery made by Dr. Judah Folkman, the Boston “cancer warrior.” As a surgeon who removed tumors, Folkman noticed that tumors are fed by webs of blood vessels, in a process known as angiogenesis. Perhaps we can find a drug to cut off the cancer tumors’ blood supply, hypothesized Folkman. His research led to a range of drugs that are angiogenesis inhibitors. But, notes Erika Hayden in the weekly science journal, Nature, “targeting the blood vessels that feed tumors is not the silver bullet once hoped for.” Some animal studies suggest these drugs may actually accelerate cancer.
Now comes news that hints at a true silver bullet for cancer that takes the form of a gene known as p53 or TP53 (the T stands for tumor suppressor, p stands for protein, and 53 is its molecular weight). The p53 gene brings to mind the World War II US fighter aircraft, the P51 Mustang, where the “P” stands for pursuit, for the p53 gene too is a “pursuit fighter.”
As early as 1979, researchers found that p53, attached to chromosome 17, suppressed cancer. It did this by signaling cells whose DNA had become defective – by becoming cancerous for example – to commit suicide.
To paraphrase the opening scene of the TV series, Mission Impossible, the p53 gene says: “Good luck, Jim. This cell will self-destruct in five seconds.” The smart p53 gene simply attaches itself to defective DNA and stops it in its tracks from reproducing. The cell dies harmlessly without having progeny.
But cancer cells are devious. They know how to neutralize or mutate p53. So instead of committing suicide, cancer cells multiply uncontrollably, ultimately spreading and – if left untreated – leading to death.
What if, researchers asked, we could find a way to keep cancer cells from neutralizing p53? What if we could get p53 to defeat cancer cells and insist that they die? Research shows that about half of the forms of cancer cause p53 to mutate and become harmless, while the other half blocks p53 by attaching it to a protein known as MDM2. When the two proteins stick together, p53 no longer functions.
Writing in the Boston Globe, reporter Gina Kolata notes that “for the first time, three pharmaceutical companies [Merck, Roche and Sanofi] are poised to test whether new drugs can work against a wide range of cancers independently of where they originated.”
Each of the three companies has a version of a drug that restores the p53 mechanism that helps badly damaged cells to selfdestruct.
These are the first clinical trials of their kind. The new drugs work by prying apart p53 and MDM2, by attaching themselves to the proteins in just the right place.
The work on p53 shows that major change has occurred in the way drug companies seek new drugs. A few years ago, I visited the R&D center of Pfizer, in Groton, Connecticut, where some 5,000 top researchers worked on drug discovery. In 2010, however, Pfizer closed the entire center and moved it to China. One reason for the move was the shift in drug discovery technology. Instead of randomly seeking molecules that had desirable effects, researchers now identify bad proteins (“target molecules” triggered by genes) and seek good proteins that neutralize the bad ones by attaching themselves to them. This new technology requires skills that older scientists simply do not have.
But, paradoxically, the shift to geneticsbased drug discovery has now brought oldfashioned biochemistry back into fashion.
As genomics (the study of genes) shifts to proteomics (the study of the proteins that genes trigger), biochemistry is required to better understand proteins.
I discussed p53 with Technion Prof.
Avram Hershko, 2004 Nobel Laureate in Chemistry. It was Hershko’s research, in conjunction with fellow laureates Prof. Aaron Czechanover and Irwin Rosen, on ubiquitin that may lead to the p53 breakthrough.
Ubiquitin regulates how and when cells die.
Its discovery led directly to the wonder drug, Velcade, which now successfully prolongs the lives of patients with multiple myeloma, a form of cancer once thought fatal.
Hershko used a colorful metaphor to explain the chemistry of p53. The cell is a kind of assembly line, he explained; it reproduces its DNA. And like all assembly lines, it has a quality control system – checkpoints that insure that cell division is healthy and normal.
If not, it self-destructs. Ubiquitin is involved in this process.
In cancer, the assembly line goes berserk and shuts off the p53 quality control mechanism, resulting in the production of bad DNA that makes cells with up to 53 chromosomes (normal cells have only 46). To keep this from happening, researchers seek a “high affinity ligand” – a good, small molecule that would attach itself to bad molecules, in just the right place, to neutralize them.
Hershko cautioned that finding such small molecules is exceedingly difficult. When you seek to neutralize big molecules, you can attach proteins to them in a number of different places. But for small molecules, like MDM2, you have just one place that works.
It is immensely difficult to find neutralizing molecules that seek that single spot, Hershko said, likening the task to shooting a bullet at a mosquito.
In folklore, a silver bullet is the only weapon capable of killing werewolves or monsters.
Finding a silver bullet for the cancer monster remains one of the Holy Grails for scientists. Researchers will find it one day; but until then, we can only lament the fact that far more resources are invested in curing cancer than preventing it.
In 2012, Israel Cancer Association Director General Miri Ziv said that six of 10 cancer deaths were preventable by early diagnosis, a healthy lifestyle, immunizations and adequately-funded national interventions (like anti-smoking programs). By this calculation, 6,000 people die needlessly from cancer every year in Israel alone. Until we get that silver bullet, why not jumpstart cancer prevention? Few social investments can match its payback.
Shlomo Maital is a senior research fellow at the Technion’s Samuel Neaman Institute.