Killing cancer

Israeli scientists are in the forefront of the war on the deadliest disease.

By SHLOMO MAITAL
The Teva Pharmaceutical Industries plant in Jerusalem. (photo credit: AMIR COHEN - REUTERS)
The Teva Pharmaceutical Industries plant in Jerusalem.
(photo credit: AMIR COHEN - REUTERS)
EVERY YEAR cancer kills a great many people in Israel and abroad. This wretched illness brings pain, heartache and suffering to those afflicted and their loved ones. It is high time we figured out how to kill cancer and a number of brilliant Israeli scientists, in Israel and the US, have made major breakthroughs. Thanks to them, one day we will turn the tables and kill this disease, instead of letting it kill us.
Cancer is a group of diseases, more than 120 of them, all of which involve abnormal cell growth. Cancer cells, instead of dying, divide uncontrollably and, if not removed or killed, end the victim’s life. Globally, there are some 14 million new cases annually and more than 8 million deaths. Worldwide, one in every seven deaths is caused by cancer. In Israel, cancer is the leading cause of death – 50 percent more people die of cancer than of heart disease.
In the next two decades, the number of persons in the world who have cancer will rise 75 percent, to 25 million annually. There are two main reasons. First, populations are aging, and second, because fewer people die at younger ages from heart disease, more survive to cancer-prone ages. For instance, according to Cancer Research UK, one in two British people will develop cancer during their lives – a shocking statistic.
In Israel, cancer is the leading cause of death – 50 percent more people die of cancer than of heart disease. There are more than 40,000 cancer deaths annually, despite radiation, chemotherapy and some 200 anti-cancer drugs. One woman in eight is afflicted by breast cancer. A major research project is studying cancer-prone genes among Israeli Ashkenazi women.
A Ministry of Health study showed that between 1999 and 2011, there was a dramatic decline in mortality due to stroke, heart disease, diabetes, respiratory illness and even accidents. Cancer survival rates have risen, but modestly. Because cancer involves abnormal cells, and because cells are more likely to be aberrant as we grow older, cancer afflicts mainly the elderly. Eight cancer deaths in 10 occurred among those over age 65, but tragically 400 children a year are diagnosed with cancer, half of them with leukemia.
By the year 2030, according to experts, the number of Israelis aged 75 and over will be 50 percent higher. As a result, because Israelis live longer than citizens of most other countries – 84 years for women, 80 years for men – cancer deaths will continue to rise, unless scientists figure out a cure. Sixty percent of cancers appear in those over age 65.
Fortunately, there have been several promising breakthroughs since I last wrote about cancer (The Jerusalem Report, February 11, 2012). Here are a few of the most dramatic ones, all by Israeli scientists.
Personalized medicine: I found a wonderful new approach in an unlikely place – the Faculty of Chemical Engineering at my university, the Haifa Technion. Chemical engineering has thoroughly reinvented itself more than any other engineering discipline. Once a field that trained engineers to run refineries and smelly chemical plants, today, chemical engineering grapples with challenges like targeted drug delivery, using sophisticated nanotechnology.
I spoke with Prof. Avi Schroeder, a graduate of Ben-Gurion University in Beersheba, who did his post-doctoral research at the famous Langer Lab at MIT in Cambridge, Massachusetts. Schroeder tackled the Achilles heel of cancer drugs. They work for some cancer patients, fail for others and you do not always know for sure whether a drug will work or not. If it doesn’t, valuable time has been lost, sometimes fatally.
“Being an engineer,” Schroeder tells The Jerusalem Report, “I thought of an engineering approach to pre-screen drugs on a personal basis before we begin a treatment cycle.” His idea is deceptively simple, similar to testing for an allergy by scratching the skin and applying a tiny amount of the allergenic material.
There are more than 200 different anti-cancer drugs, most of which are hugely expensive. Roche, a Swiss-based firm, sells $31 billion worth of cancer drugs yearly, followed by Novartis ($11.2 billion), Amgen ($6.8 billion) and Celgene ($5.5 billion). Treatment for a single individual can cost as much as $150,000 or more. While Teva doesn’t provide a breakdown of sales by drug type, Israel’s global pharma giant claims to be in the top 10 suppliers of cancer drugs in the huge US market.
According to the American Association of Retired Persons, 11 of the 12 new cancer drugs approved in the US in 2012 were priced above $100,000 annually; a 20 to 30 percent co-payment by the insured person can make these drugs unaffordable even for well-insured patients. With populations aging in the West, expensive cancer drugs will either be budget-busters or be confined to only the privileged wealthy. There has to be a better way.
Each individual may react differently to each drug, depending on his or her genetic makeup and the type of cancer they have, and even depending on their gender. For instance, we now understand that women react completely differently to many drugs than men – and America’s FDA now requires drug testing to include gender in the clinical trials, both with mice and with humans, to see if there are indeed differential gender effects.
In Schroeder’s approach, the cancer patient is given a battery of drugs in miniscule doses – and then tested to see which, if any, actually reach the tumor, penetrate the cancer cells (which have clever defenses) and kill them. Schroeder creates nanoparticles containing drugs “bar coded” with DNA. The process of attaching DNA to each molecule of the drug is not expensive anymore, because DNA has become quite cheap. These nanoparticles are injected into the patient’s bloodstream where they travel around the body. When they identify a tumor, the drug particles penetrate its cells through micro-fissures that cancer cells typically have, like a very short person ducking under a turnstile.
The drug is then released into the cancer cells. Some will work and kill the tumor; some won’t. To find out which is the case, the tumor is biopsied with a needle and cells are removed and examined individually. The dead cells are separated from the living ones and a kind of cell “autopsy” is performed to determine cause of death, as Schroeder explains, to see “which drug bar code is the most associated with killing cancer cells and which is not.”
So far, testing is in the preclinical stage. Schroeder is looking for financing to bring the idea to market. The beauty of his method is that it is based on drugs that already exist. With it, expensive cancer drugs will not be used in vain.
Cancer immunology: Use of the body’s own immune system to kill cancer cells was chosen in 2012 as the “Breakthrough of the Year” by the editors of Science, the academic journal of the American Association for the Advancement of Science. One day soon, chemotherapy may be replaced by immunotherapy. Instead of poisoning cancer (and our own body), we may be able to trick cancer cells, which are good at defeating the body’s own T-cells (a kind of white cell that seeks out and kills invading germs and viruses, as part of our immune system). Researchers now know how to enable our T-cells to kill cancer cells before they become tumors or even after.
The new approach is metaphorically like training cancer-killer cells first to spot cancer, and then kill it, by teaching them to recognize the enemy and then, giving them “martial arts” skills to destroy it.
Some of the most advanced work in the world on cancer immunology was done by Prof. Leah Eisenbach, at the Weizmann Institute, Rehovot. And an Israeli company known as Compugen developed antigens (antibody generators) proven useful against cancer, selling two of them for hundreds of millions of dollars to Bayer, a pharma giant.
Tel Aviv University Prof. Yosef Shiloh recently won Norway’s Olav Thon Foundation Prize for his trailblazing research on cancer genetics, showing how and why normal cells turn into cancer. Earlier, Technion Nobel Laureate Prof. Avram Hershko, with his former student Aaron Ciechanover, showed how “ubiquitin” causes damaged cells to die but fails to do so for cancer cells, leading to the development of the anti-cancer drug Velcade, which treats multiple myeloma.
Ciechanover is currently president of the Israel Cancer Society. A team of researchers in his lab recently discovered how a protein that normally encourages cancer, known as p50, acts like “Dr. Jekyll and Mr. Hyde” (as he told the daily Haaretz). Large doses of p50 transform it from the evil Mr. Hyde into kindly Dr. Jekyll, producing other proteins known to suppress cancer. Their results were published in the leading journal Cell. A cancer drug may emerge, though it will take years, Ciechanover cautioned.
Flying a Kite: In 2009, Dr. Arie Belldegrun, an Israeli who trained at the Weizmann Institute, founded Kite Pharma, a biopharmaceutical company that develops T-cell therapies that help one’s own body recognize and destroy tumors, in Santa Monica, California. Belldegrun is the company CEO. In June 2014, Kite’s initial public offering of shares raised $147 million, followed by a second round of financing that brought in $217 million. Kite Pharma’s technology is known as eACT and is supported by Kite’s strategic partner, the US biotech giant Amgen. Clinical trial results of Kite cancer drugs have been spectacular.
Additional breakthrough research in this realm was done by Prof. Zelig Eshhar, of the Weizmann Institute, together with Dr. Steven Rosenberg, of the US National Cancer Institute. They tackled the difficult problem that, unlike viruses or germs, cancer cells are part of the human body itself, hence good at avoiding the lethal T-cells sent by the body’s immune system. The two researchers have genetically modified T-cells to enable them to identify a protein that exists in concentrated form on the exterior wall of cancer cells, but less so on normal cell walls. These modified T-cells “open” cancer cells like a key opens a locked door, enter them and destroy them.
Electrocute cancer: In some states in the US, convicted murderers are put to death by electrocution. A Technion Medical School researcher, Prof. Yoram Palti, figured out how to do the same to cancer cells – a far more humane use of electricity. A few years ago, I interviewed him to learn how he came up with his path-breaking idea.
“For over 30 years,” he told me, “I was totally committed to basic science, specifically, to understand the biophysical mechanisms responsible for nerve and muscle function. After running the Rappaport Institute [an independent biomed institute linked to the Technion’s medical school] for a decade, I decided to change course and try to solve serious medical problems.
“I looked for a treatment for cancer based on a biophysical basis, rather than pharmacological, because biophysics is what I know best. The potential solution came when I reverted 40 years back to my PhD thesis that studied the electrical field distribution in living tissues. In about the year 2000, it occurred to me that I can design electric fields that would damage dividing [cancerous] cells (due to their hourglass shape) and not harm normal ones. I began Novo-Cure in my basement.”
Palti’s “Optune” device puts an electromagnetic field around the brain (with a cap) or around the lungs (with a vest) and stops tumors in their tracks by exploding the narrow “waist” of dividing cancer cells each time they try to split and proliferate. Novocure has raised more than $250 million in investments, has 150 global treatment centers and, spectacularly, its Stage 3 clinical trials were ended prematurely, a rare event, not because of failure, but because results were strikingly successful.
Palti, like me, is well into his 70s. Not many great start-ups are founded by senior citizens. I asked him what his secret was. “One loses capabilities with age,” he told me, “but, on the other hand, the wisdom and insight gained can be directed to better utilization of capabilities. The main thing is to realize this, take advantage of it, and… keep pursuing, keep the drive!” The Novo-Cure device can halt previously untreatable glioblastoma brain tumors, and has been successful even in halting hard-to-cure lung cancer. Keeping cancer from metastasizing (spreading) can save many, many lives.
Gold-plated cancer: An Israeli Arab from Nazareth, Dr. Amal Ayoub, founded Metallo Therapy, a biomed start-up that introduces gold nanoparticles into cancer tumors. She holds several patents. According to Ayoub, a mother of two, her invention helps produce sharper diagnosis and staging of the cancer, better targeting of radiation and better evaluation of chemotherapy or drug therapy. Her breakthrough came after a decade of working in cancer radiation therapy and, so far, she has raised $1.2 million from the Office of the Chief Scientist, Arkin Holdings and an Israeli Arab incubator.
Ayoub is completing safety studies in animals and hopes to begin clinical trials soon. According to the daily Haaretz, she hopes “the 400-million-strong Arab world – including dollar-rich Saudi Arabia and United Arab Emirates – will be interested [in her technology].”
A great deal of cancer research is funded by America’s National Cancer Institute (NCI). From 2005 through 2014, the NCI’s annual budget averaged close to $5 billion. Some Israeli researchers, too, have benefited. And, doubtless, some of the NCI-funded research has saved lives.
However, when I see these vast sums of money, I think of the former Jewish mayor of the Brazilian city Curitiba, Jaime Lerner. “If you want true creativity,” he used to say, “knock two zeros off your budget.” He took over a bankrupt city and without money cleaned up its garbage and parks, and revitalized its downtown with creative ideas.
With few exceptions, Israeli cancer researchers have very few zeros in their budgets. As a result, they have had to be creative, to think out of the box. The result may be that one day Israeli scientists’ creativity will soon show the world how to kill cancer instead of letting it continue to kill us.
The writer is senior research fellow at the S. Neaman Institute, Technion and blogs at www.timnovate.wordpress.com