By Jenny HazanAccording to the latest estimates from the Prostate Cancer Foundation, more than 218,000 men in the United States alone will be diagnosed with prostate cancer this year. The disease strikes one in six men. If detected early enough, there is a high success rate with traditional treatments such as radiation, chemotherapy, surgery (prostatectomy), hormone therapy, cryotherapy, and high-frequency radiotherapy (Hi-Fu). But the side effects of such treatments can be severe, requiring patients to undergo long and painful recoveries and in the long-term, causing impotency or incontinency. What's more, in all cases the collateral damage caused by one treatment closes the door to subsequent therapies, so healing is hope-ess in cases where the cancer is not cured in one shot or metastasizes to other parts of the body.
At least that was the prostate cancer treatment landscape until the beginning of 2000, when the research outcome of a unique team of scientists at the Weizmann Institute of Science in Rehovot, Israel, had appeared to enable a better remedy. Nine years earlier, the director of the Weizmann Institute's Avron-Wilstatter Minerva Center for Research in Photosynthesis, Dr. Avigdor Scherz, and the head of the Institute's Department of Biological Services, Dr. Yoram Salomon, helmed jointly the basic idea. By 1995, they had already gathered a relatively small group of chemists, biologists, pharmacologists, physicians, and physicists who had proven their novel concept. At the end of 1996, industry joined in to boost up the pharmaceutical development. Three years later, following an extensive basic and pre-clinical research, a new compound and tailored technology emerged.
TEAM SCIENCEThe treatment is nontoxic and there are no long-term side effects. It takes only 10 minutes and is a non-invasive, potentially outpatient procedure. Best of all, the remedy doesn't cut patients off from subsequent treatments. In clinical trials, 50% of patients have been cured with a single treatment and possibly 70-80% may be cured after two. It is called Vascular Targeted Photodynamic Therapy (VTP), and it may revolutionize the way science approaches cancer treatment.
How did this small team come so far so quickly? What is the secret to their solution? How did they manage to succeed where other major universities and research institutes have failed?
According to Salomon, it is all a matter of opening the lines of communication between disciplines. Whereas classical formats of multidisciplinary scientific research consist of interactions between whole departments at different institutes around the globe, the Weizmann Institute team gathered representatives from each discipline and put them shoulder-to-shoulder in the same lab—an innovative new approach to scientific collaboration.
"Wherever you have contact between disciplines, that's where new ideas form because you are inspired by your environment and you can sometimes bridge concepts that you otherwise wouldn't be able to bridge," says Salomon. 'The idea for VTP never would have come up if we hadn't sat together and bridged the different disciplines we're in."
DR. AVIGDOR SCHERZThe story of bacteriochlorophyll (Bchl)-VTP begins in 1990 in a hallway of the Ullmann Building at the Weizmann Institute, where Dr. Yoram Salomon, who at the time was conducting research on the role of hormones in tumor biology as a professor in the Department of Biological Services, ran into his younger brother's former high school classmate, Dr. Avigdor Scherz, then an associate professor in the Institute's Department of Biological Chemistry.
Driven to cure the cancer of a recently diagnosed member of his own family, Scherz had switched the focus of his lab from plant photosynthesis to chlorophyll-based cancer drugs. At this chance meeting in the corridor, he asked Salomon whether he had any cancer cells on which to test his new development. Salomon offered Scherz melanoma cells. "Our collaboration began at that moment," recalls Scherz.
By 1991, the two professors had co-opted their labs and gathered together a team of some eight scientists representing different disciplines and varying developmental stages in the life of a new treatment—from basic research to the pharmaceutical industry to clinical application.
"What we developed is a kind of closed circle, wherein there was a very intimate level of interaction between all the branches," explains Scherz. Their idea was to create the ideal feedback mechanism, whereby expertise from all areas could inform each other, creating the most efficient route to test new ideas and discover solutions. "We didn't just want the group to be multidisciplinary in the sense of having different people from different disciplines communicate together; we had our sights set on developing in all scientists involved a multidisciplinary way of thinking. Later on this was accomplished by a daily and completely transparent communication with the industrial partner's experts. This model for collaboration represents an entirely new scientific approach."
The concept of the unique new lab's development, however, was not entirely new. VTP takes its basic idea from its predecessor, Photodynamic Therapy" (PDT). In classical PDT, a cancer patient is injected with a light-sensitive pigment-based chemical ("sensitizer") that when exposed to light forms radicals that in turn excite oxygen molecules to oxidize, thus creating a toxic internal environment that kills tumor cells.
While it is an effective technique, the problem with classical PDT is that the sensitizers used show no tissue or organ selectivity, need hours to days to absorb into the tumor cells before treatment, and slowly exit the body afterward. The result is that patients continue to be sensitive to regular light and cannot go outside for several weeks or months after the treatment; since they are at risk of being burned by the light of the sun. Moreover, current sensitizers enable treatment of shallow tumors because of their limited physico-chemical properties.
Until Scherz and Salomon's lab, scientists had not figured out a way to harness effectively the photosensitization capabilities of chlorophyll in the photodynamic treatment, since in their native form these molecules present extremely low solubility disabling their use as vascular photosensitizers. Scherz's lab discovered ways to modify the hydrophobicity of the chlorophylls. But there was still work to be done. Although the chlorophyll-based drug was a big improvement over existing sensitizers, the type of light (i.e., sunlight) required to excite it could only penetrate into tissue at relatively shallow depths. Hence, Scherz proposed the use of a different kind of chlorophyll, namely, a type of Bchl that exists in the depths of the ocean and relies on infrared light (which can penetrate more deeply into human tissue) to photosynthesize. It turned out, in experiments conducted in the two labs, that this discovery enabled the first successful treatments of melanoma tumors and consequently, patent application in 1993 for non-toxic chlorophyll-based sensitizers to be used in PDT.
"It had a lot of advantages over the pigments that were used at the time," says Scherz. "Namely, chlorophyll doesn't stay in the system very long. After all, it's in every piece of lettuce we eat."
In 1995, Scherz and Salomon's lab patented the first PDT containing Bchl-based sensitizer, and in 1999 a more water-soluble version of it: Tookad. This name, which is the Hebrew wording for "the center or warmth of light," was coined after a passage in the Bible, that deals with a cure delivered by God to humans. The birth of Tookad marked the dawn of Bchl-VTP and a possible new age of cancer management.
DR. YORAM SALOMONAccording to Dr. Salomon, who did his B.Sc, M.Sc, and Ph.D. in biochemistry at the Hebrew University jn Jerusalem before becoming a professor at the Weizmann Institute, the unique kind of collaboration that gave rise to Tookad would not likely take place outside of the Weizmann Institute or outside of Israel, for that matter. "I have to give the Institute itself credit because they made our collaboration very easy," he says. "There are no barriers there. It's a very cooperative environment."
"We use our knowledge and intuition to find solutions that work, then go backward to understand in greater detail why they worked. Most scientists around the world function in the opposite way..."As for Israeli science in general, Salomon says that the Institute's approval of the lab's avantgarde approach is indicative of a general trend in the country's scientific culture. "Rather than conduct years and years of testing on chlorophyll, for instance, we just jumped to the end and said, 'Does it work? Good. Now, let's see how it works,' he explains. "We use our knowledge and intuition to find solutions that work, then go backward to understand in greater detail why they worked. Most scientists around the world function in the opposite way, so we really operate against the dogma."
It's for that reason the lab's initial findings, while extremely impressive, were rejected out-of-hand by the scientific community at large and why it took so long—nearly five years—to get their methodology tested in clinical trials.
"Initially, we had lots of problems; much of what we did was not accepted by colleagues in the field. Our papers were refused by labs around the world; they wouldn't even test it before they rejected it," says Salomon.
For instance, because classical PDT required a lag time of 24 hours or more between injection of the sensitizes and illumination of the infected tissues (in order for the drug to penetrate into the cells), the scientific community was apt to reject VTP's biochemical mechanism, which required immediate or simultaneous illumination in order to be effective. "We had to work very hard to change the scientific community's status quo," he says.
It wasn't until Scherz and Salomon convinced Dutch pharmaceutical company Steba Beheer NV to come on board in 1996 that other institutes agreed to start testing Tookad in pre-clinical trials. Says Salomon, "Slowly, but surely, our methodology was taken seriously."
Rather than classical PDT, which targets the tumor cells themselves, VTP targets the blood vessels that supply the tumors. According to Salomon, the idea to cut off blood flow to the tumor was also not a new one. But the problem with the chemicals used in anti-angiogenic therapies (i.e., therapies that inhibit the growth of blood vessels) is that the drugs used only antagonize the creation of the vessels, but don't end their construction completely. When the treatment stops, the blood vessels begin to grow again. In conjunction, there is the issue of drug resistance.
By contrast, VTP completely destroys the blood vessels that feed the tumor; the tumor becomes schemic, necrotic, and is finally eradicated and carried out of the body by the immune system.
With VTP, doctors first conduct an MRI and ultrasound to map out the tumor and establish a plan of attack. The drug is infused into the bloodstream via an IV, and while it is continually distributed throughout the body, the tumor area is illuminated with a series of carefully placed fiber optic lasers (so as to confine the illumination as close as possible to the treated zone). Within approximately 10 minutes, the illuminated tumor blood vessels narrow and fill with clots. Blood flow to the tumor stops. Five minutes later, more than 90% of the drug is cleared from the bloodstream.
The best part is that there are no side effects to VTP. There is absolutely no damage to tissue or cells that are not illuminated, and none of the three elements that comprise VTP— Bchl, oxygen, and infrared light—are toxic in and of themselves. But together, they're a lethal combination—for tumors.
Currently, Tookad is being tested in advanced Phase 2 clinical trials in France (for a degenerative eye disease called macular degeneration); in the UK, on prostate cancer patients with no previous treatment history who chose VTP as their first therapy; and in Canada, at Princess Margaret Hospital in Toronto and Royal Victoria Hospital in Montreal, where they are conducting "salvage therapy" aimed at curing patients with a recurrence of prostate cancer after first treatment radiation. Phase 3 testing is scheduled to take place this summer.
DR. ALEXANDER BRANDISWhile those clinical trials are taking place, the Weizmann Institute group continues to develop an arsenal of new compounds, aimed at different types of cancer, regimes of treatment, and diagnostics.
The chief molecular engineer who is enabling the synthesis of the new compounds is Dr. Alexander Brandis, a Ph.D. in chemistry and technology of natural products from the Lomonosov Institute of Fine Chemical Technolqgyjn Moscow, Russia, and a double postdoctorate in biochemical studies on chlorophyll and bacteriochlorophyll from the Weizmann Institute in Scherz's lab.
For Brandis, working on the VTP project came as a welcome surprise. It was merely by chance that he had heard of the Weizmann Institute team and their work at one of the first meetings that was allowed to take place of the USSR's Society of Jewish Scientists and Engineers in Moscow in 1991.
"When Gorbachev came into power, there were a lot of new things in the air, and a lot of Jewish societies started in Moscow. This was one of them," explains Brandis. "I participated in the Societies' Israel Science Day, and just happened to pass my CV to one of the representatives from the Weizmann Institute who was there."
Brandis had been working on compounds for PDT for several years and, in fact, engineered one of the first sensi-tizers for use in PDT. "Photodynamic therapy was extremely interesting to me because it was a new area with so many potential applications," he says.
On the afternoon of Israel Science Day, Brandis received a call from the Weizmann Institute representative encouraging him to apply to do his postdoc in Rehovot. "It was Israel's Independence Day, and my father's birthday," recalls Brandis. "I will never forget that day."
Brandis moved to Israel from Moscow in 1992 to join the fledgling team. "From the moment I met Scherz, we started coordinating," he says. "It was an ideal adoption. I found exactly the place where I had to be to continue my career."
The Israeli approach to scientific research was a shock to Brandis's system. "Although our lab in Moscow was a very well-established alma mater, we had very little direct contact with labs around the world," explains Brandis. During that time in the USSR, scientists had access to research papers from around the globe but did not conduct many cooperative efforts with scientists abroad. "For me, working in Israel opened up this whole new world of international collaboration. After 15 years, this global approach is still extremely exciting to me."
The VTP team took that collaboration to a whole different level for Brandis. "In Moscow, my lab used to synthesize a compound, then test it, then send the sample to another institute, then wait for their reply," he explains. "The first time I came to the lab at Weizmann, it was so strange to see all the scientists multitasking. Here, you don't have a department where everyone does his own work, individually; you have a few people who do a lot of different things.
"In our group now, the close proximity between disciplines not only makes the process much faster, but the collaborative work sharpens your intuition. Getting feedback every day and discussing problems in real time makes a huge difference to one's state of alertness."
That's not to say that the experience hasn't had its challenges. While he loves the multidisciplinary structure of the group, it also makes creating compounds more difficult, since there are more factors to consider. "Rather than just synthesize new compounds that will be effective from a physical standpoint, we have to think ahead about whether they will be viable from a clinical and pharmaceutical perspective," explains Brandis. 'The compound may be effective, but what's it worth if it causes bad side effects, or if it's too expensive to be mass produced?"
Since so many cures have been serendipitously discovered (i.e., while searching for a cure to one affliction, a researcher stumbles upon a cure for a totally unrelated problem), Brandis says the group's new approach to contextual thinking is extremely challenging, since his natural inclination is to follow' his molecules to see where they lead. "Participating in the group has required a real switch from question-oriented research to objective-oriented research."
On a personal note, adjusting to Israel has also been a big challenge for Brandis, who although Jewish, had never been to Israel until he came to the Weizmann Institute. "Coming to Israel was itself an adventure. It was very strange for me to go from living in Moscow, with 15-million people, to living in Rehovot," says Brandis. "But, I met my wife here and now we have two daughters. I am very happy."
EFRAT RUBINSTEIN, M.Sc.One of the most intriguing new compounds the team is working on is a more sophisticated version of Bchl, one that exclusively targets tumor blood vessels so that the drug does not have the potential to affect all tissues that are subjected to light subsequent to infusion. Instead, it only affects tumor vessels, so it's possible to hone in even closer on the targeted tissues.
The woman behind this new innovation-in-progress is Efrat Rubenstein, one of 14 Ph.D. students hailing from disciplines including computational chemistry, chemistry, biology, and pharmacology. These students comprise the basic research arm of the group and whom Scherz „ dubs "the team's lifeline."
"My new development capitalizes on the fact that some tumor blood vessels—including those that feed brain tumors, metastatic breast, melanoma, and lung tumors—have special receptors," explains Rubinstein, a student of both the Institute's Departments of Plant Sciences and Biological Regulation. "I am adding a sort of 'homing device' to the sensitizer in order to target these specific receptors.
"The benefit of this new drug is that because it's more directed, there can be no accidental peripheral damage to 'good vessels' and tissues surrounding the tumor vessels, and it will spare as much as possible the collagen supporting matrix, which plays a big role in the body's natural healing process."
Since commencing her Ph.D. in 2001, Rubinstein has synthesized, developed, and tested in vitro a large number of VTP agents. "Before you can check the agents on animals (in vivo) you have to test them extensively on cell cultures (in vitro)," explains Rubinstein. "But there is a problem in the correlation: The cell environment is very different from the animal environment and oftentimes what responds in vitro does not respond or work in vivo."
According to Rubinstein, the process of in vitro testing can be extremely taxing. "It's very hard mentally because you experience so many disappointments along the way." She says that there is often no correlation between what should work theoretically and what does work in practical application. "You have to be very strong to continue."
'This sort of frustration is the real test of one student or one scientist versus another," comments Scherz. "Either you take it in stride and learn to benefit from it, or it breaks you down."
It's precisely because there are so many disappointments that the moments of accomplishment are so exhilarating. For instance, Rubinstein says she will never forget the moment that one of her sensitizers elicited a positive response to a cancer sample. "I was at the special lab in Jerusalem, about halfway through testing some 250 samples, all of which had produced a flat line," she recalls. 'Then I put this cancer tumor sample into the machine and the line started to peak, indicating that a reaction was indeed taking place.
"At first, I thought the machine was broken," she says. 'Then I tested and retested and retested again, and I realized it wasn't broken at all. I was onto something! As long as I live, I will never forget that moment. It was August 23, 2004. We submitted the patent one year later."
Rubinstein, a new mother of two, completed her B.Pharm. at Hebrew University in Jerusalem in 1995. Straight out of school, she began to work at Super-Pharm Pharmacy in Rishon LeZion, a position she kept throughout the duration of her M.Sc. in pharmacology at Tel Aviv University, and right up until she started her Ph.D. "I wasn't happy just to work in a pharmacy," she says. "Something was always missing. After my master's, I understood that I had to do research full-time, but it had to be in a field with clinical applications."
That's when she discovered the group at the Weizmann Institute. "I can't think of any other place where I would be able to be involved, step-by-step, from the very beginning of separating molecules and synthesizing them in vitro to seeing my agents being used in pre-clinical and clinical applications," she says. "It is impossible to describe the joy of nurturing this little molecule into something that really works. Being part of this group has been a dream come true."
According to Rubinstein, who will submit her Ph.D. thesis on April 30, 2007, being part of the group has been a very special experience for other reasons, too. "When I look at the papers and abstracts from the big conferences and see how many authors and university departments and research institutes are involved, and how much support projects receive from big companies, it makes me very proud," she says. "We are only a little group, a few people, and we are not accompfishing less than them.
"When it comes to finding a cure for cancer, there is still a long way to go," she says. "But we have already made a contribution that has been way beyond our expectations."
DR. NATALIA KOUDINOVAAs Rubinstein says, there is a big difference between in vitro and in vivo testing. That's where Dr. Natalia Koudinova comes in. As head of Steba Israel's Biological Unit, Koudinova serves as an essential conduit between the lab at Weizmann and the pharmaceutical company.
Since she assumed the position three years ago, Koudinova has screened dozens of compounds in vivo, between those produced by Steba's R&D Department and those produced by the lab at the Weizmann Institute. Altogether, she has recommended only six for pre-clinical or Phase 1 clinical trials.
According to Scherz, Koudinova is an essential member of the Weizmann team, since she is in a very unique position to diffuse the tension inherent between the lab and the pharmaceutical company, or between research and industry related primarily to issues of intellectual property (IP). "Dr. Koudinova and the rest of the Steba team bridge a very important gap and replace natural hostility with constructive cooperation," says Scherz. "Without this collaboration, several of our compounds might never have made it into circulation and the development of others would take forever."
Like Brandis, Koudinova came to the Weizmann Institute group quite by accident. Her husband, a neuroscientist from Moscow, was invited to participate in a project at the Department of Brain Research at the Weizmann Institute in 1997. She followed him to Israel. After working for two years on her postdoc on Alzheimer's disease at the Institute's Department of Neurobiology, Koudinova, a medical doctor who completed her Ph.D. on lipid metabolism in Alzheimer's at the Peoples' Friendship University in Moscow, met Dr. Salomon.
"I never anticipated I would end up in the field of PDT," says Koudinova. "But before I knew it, I was developing the animal prostate cancer and bone metastases models." It was Koudinova who conducted the first study that showed that Tookad was a successful treatment for human prostate carcinoma and bone metastases. More than 80% of the animals used in preliminary tests were completely cured of large
tumors-via VTP. It was these tests that became the backbone of Koudinova's second postdoc, which she completed in 2004. Just after she finished her degree, her Israeli visa expired. "All of a sudden, it looked as though I would have to leave Israel, which was such a pity because I loved Israel and the group and I didn't want to go anywhere else," recalls Koudinova, the team's only non-Jewish member. "Although science is a very international thing, when you are working in a lab, you are not just doing science; you are working with people," she says. "The lab environment at the Weizmann Institute was unlike any other lab I had worked in before. It was an open, communicative, social environment. I really enjoyed it."
Salomon and Scherz took action on Koudinova's behalf and wrote letters to the Ministry of the Interior appealing to the authorities to grant Koudinova an extension. "She was a key member of our team," comments Scherz. "The amount of knowledge and skills that she had acquired over the years was essential for the fast development of new products. It was really in the best interests of the State of Israel to let her stay." Koudinova was awarded temporary residency (giving her three more years) in 2004. "Finally, I could breathe a sigh of relief," she says. "I was very lucky."
Around the same time, Steba decided to establish an independent affiliate lab in Israel almost exclusively geared to supporting new research and development in the field of VTP. The timing couldn't have been more perfect," says Koudinova.
Then three years later, at the start of 2007, Koudinova found herself in a similar pickle. "Again, we applied to the Ministry of the Interior," she says. "Only this time, I got extra lucky and they awarded me permanent residency. So, now I can live the rest of my years in Israel worry-free.
"It's been strange to have my professional scientific life tied in so closely to my personal life," she notes. "But in the end, I love my work, I love this country, and I know that this is where my family belongs."
DR. SMADAR SCHREIBERAccording to Salomon, the sort of tension that exists between the research and pharmaceutical fields of medical development tends to exist similarly between the research and clinical fields. In the case of VTP, which requires far fewer human and hospital resources—and, ultimately, less expense tharr traditional cancer therapies—this tension is particularly pronounced. "In medicine, there is usually opposition to new approaches," says Salomon, who explains that there is also the issue of having to train in order to learn how to implement the new technique.
Dr. Smadar Schreiber is a clear exception. The practicing doctor in the PDT Unit at the Assaf Harofe Medical Center near Tel Aviv, Schreiber's primary contribution to the team is her firsthand experience.
"I am actually putting current photodynamic technology into practice," says Schreiber, who uses PDT to treat dermatological ailments such as skin lesions, viral warts and other viral lesions, psoriasis, acne, and of course, cancer. "The patients react very well to the treatment. Side effects are local and transient, and although there is usually an inflammatory reaction for a few days following the treatment, it only takes three or four weeks after one treatment for the lesions to disappear completely and to be replaced with heafthy, younger-looking skin."
In addition to bringing firsthand PDT experience to the group, Schreiber was the first to test Tookad-VTP in pre-dinical trials. "I was the first to test the mode of application and successfully demonstrate that it worked against tumors in animal models," explains Schreiber. "I think this was a very important contribution to the group."
It's worth noting that Schreiber did not get her start in PDT. Since she graduated from medical school at the Technion Institute of Technology in Haifa in 1986, she worked first as a physician in the IDF, then as a researcher at a manufacturer of light-based devices for medical and cosmetic purposes, and finally as a developer of clinical protocols for doctoral students around the world. It wasn't until she began her residency in plastic surgery at the Weizmann Institute in 1997 that all of her myriad work experience seemed to come together. Before she knew it, she had extended her basic science requirement into a Ph.D. project on the effects of bacteri-ochlorophylls on tumors and became a vital member of the VTP team. "I never thought I would end up in this field," she says. "But what I am doing now really is a combination of everything I have learned."
According to Schreiber, this flexibility to combine the various elements of her knowledge base into one useful application is unique to Israeli science. "The standards of science and technology are very high in Israel," says Schreiber. "At the same time^there is always"a. place for innovation and the opportunity to pursue radically new ideas."
VTP is one such pursuit. "Photodynamic treatments have such great potential. What is being done now is only the beginning; it is going to evolve to apply to many medical specialties and many different usages," says the mother of three from Gan Hatikvah, who names gastric cancers, internal infections, restenosis, hema-tology, and melanoma among the likely future applications.
To date, VTP has been tested on colon carcinomas, prostate cancers, sarcomas, liver cancers, breast tumors, brain tumors, pancreatic cancers, and various metastases. According to Scherz, the group's immediate objective over the next two years is to cover the entire field of prostate ailments, from cancer and metastases to enlarged prostate and benign prostate treatment at various stages. After that, the team intends to tackle nonlocalized cancers such as leukemia. "Right now, we can only use this method to treat cancers wherein we know their location," explains Salomon. "Cancers without specific locations are on our list of upcoming challenges." "But," says Scherz with a hopeful smile, "the more we advance, the more the possibility for future developments and future applications opens up."
"In the end, one thing is certain," adds Salomon. "The more we collaborate, the greater our chances of success".
Source: Jenny Hazan. Cooperating for a cure. Lifestyles International edition: www.lifestylesmagazine.com (May 2007) pp.33-39Labels: Rehovot Hitech, Weizmann Institute
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