By: Prof. Shlomo Maital

How close are we to finding a cure for cancer? Forty years after U.S. President Richard Nixon declared war on cancer in his State of the Union address, and after an estimated $3 trillion invested in research and treatment in the U.S. alone, there is both bad news and good news.

First, the bad. Cancer remains the biggest killer in Israel. Of some 40,000 deaths yearly, one in four, or about 10,000,  is due to cancer, 60 percent more than die of heart disease. Worldwide, the World Health Organization reports that 12.7 million people are diagnosed yearly with cancer and over 7 million die from it. Of those, 3.4 million cancer deaths, almost half, are due to smoking.

Since 2000, cancer deaths have been rising in Israel, owing mainly to lifestyle (e.g., smoking, obesity and alcohol) 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 Health Ministry report shows that Israel has among the highest survival rates among cancer patients in the West. For males, 61 percent survive cancer after a five-year recovery period, and for females, 67 percent. One reason for this pro-female 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 in 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.

The really good news is that at long last, scientists may be on their way to finding a ‘silver bullet’ – a cure for all cancers. Here is why.

There are over 120 different types of cancer. So far, treatment has been highly specific to individual types of cancer. 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 Report a new approach to curing cancer, invented by Technion Prof. Yoram Palti, that ‘explodes’ cancer cells when they divide, by placing an electromagnetic field around the offending area in the body. When the walls of a cancer cell grow thin as it divides, the electro-magnetic field ruptures them and kills the cell. Palti’s startup, Novocure, has since successfully passed clinical trials for its device, to treat hard-to-treat brain tumors and lung cancer.

Another hoped-for silver bullet was the discovery of Dr. Judah Folkman, the Boston ‘cancer warrior.’ As a surgeon who removed tumors, Folkman noticed that tumors had webs of blood vessels feeding them, a process known as angiogenesis. Perhaps we can find a drug to cut off cancer tumors’ blood supply? hypothesized Folkman. His research led to a variety 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 cancer silver bullet. And it 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). p53 brings to mind the World War II fighter aircraft the P51 Mustang, where the “p” stands for pursuit. p53 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, for example by becoming cancerous, to commit suicide. p53 tells cells, to paraphrase the opening scene of the TV series Mission Impossible: “Good luck, Jim. This cell will self-destruct in five seconds.” Clever p53 simply attaches itself to defective DNA and stops it in its tracks from reproducing itself. 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 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 cancers cause p53 to mutate and become harmless. 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 reports 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 has a version of a drug that restores the p53 mechanism which helps badly-damaged cells to self-destruct. 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. Some 5,000 top researchers worked there on drug discovery. But in 2010 Pfizer closed the entire center and moved it to China. One reason 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 proteins by attaching themselves to them. This new technology requires skills that older scientists simply do not have. But paradoxically, the shift to genetics-based drug discovery has now brought old-fashioned biochemistry back into fashion. As genomics (study of genes) shifts to proteomics (study of the proteins that genes trigger), biochemistry is needed to better understand proteins.

I spoke about p53 with Technion Prof. Avram Hershko, 2004 Nobel Laureate in Chemistry. It was Hershko’s research, together with fellow Nobelists Prof. Aaron Czechanover and Irwin Rosen, on ubiquitin, that may directly 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  those with multiple myeloma, a form of cancer once thought fatal.

Hershko uses a colorful metaphor to explain the chemistry of p53.  The cell is a kind of assembly line, he explained. It reproduces its DNA. 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. Bad DNA is produced, 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 will attach itself to bad molecules, in just the right place, to neutralize them.

Prof. 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 hard to find neutralizing molecules that seek that single spot, like shooting a bullet at a mosquito.

In folklore, a silver bullet is the only weapon able to kill werewolves or  monsters. Finding a silver bullet for the cancer monster remains one of the Holy Grails for scientists. One day researchers will find one.  Until then, we can only lament 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 are 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 yearly in Israel alone. Until we get that silver bullet, why not jumpstart cancer prevention? Few social investments can match its payback.

This article was originally published in the Jerusalem Post Marketplace on January 7, 2013.