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Fighting Cancer at the Technion

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The Growing Threat

In English, Hebrew or any other language, no word evokes more fear than “cancer.” More than half a million Americans now die from the disease in a typical year, and more than one in three will develop the disease during their lifetimes.

And yet we hear that there is hope, that cancer is no longer a death sentence, that it can be beaten or lived with. That hope continues to grow as experts around the world use new tools to trace cancer’s origins and develop plans of attack. 

Scientists at the Technion representing traditional fields of medicine such as chemistry and biology, as well as diverse new specialties including genetics, nanotechnology and bioengineering see cancer research as one of the institute’s leading missions.  The Technion’s David and Janet Polak Center for Cancer Research and Vascular Biology and the recently launched Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, bring together the best minds from diverse fields in the quest for successful treatments.

Major Breakthroughs

At the Technion Faculty of Medicine and many other departments, this commitment to the fight against cancer has produced notable advances in our understanding of how the human body stays healthy and how this process breaks down.

Why does previously normal cell division begin to rage out of control, and how can the resulting invasion of deadly cancer cells can be defeated? Here are three pioneering lines of research where Technion scientists are leading the way:

1) Ubiquitin and You

While most researchers were focusing on how living beings build up proteins, Nobel Laureates and Technion Professors Avram Hershko and Aaron Ciechanover decided to swim against the tide. They looked instead at the flip side of the process: how the body destroys proteins that are no longer useful.

Professors Hershkon and Prof Ciechanover
Professors Hershko and Ciechanover

And in doing so, as Prof. Ciechanover puts it, “We discovered the process by which the body exercises quality control.” It is a crucial quality control process that when running smoothly keeps the body healthy, but when gone awry can lead to cancer.

Specifically, the pair discovered a molecule they called ubiquitin, which fastens to a protein, signals that it is to be destroyed and accompanies it to a kind of cellular waste-disposal unit.

Profs. Hershko and Ciechanover, along with Dr. Irwin Rose of the University of California-Irvine, won the 2004 Nobel Prize in chemistry for shining this spotlight on how cells clean house. It’s the first time an Israeli has ever been awarded the Nobel Prize in science - but far more important is the hope their discovery has raised in the fight against cancer.

Thanks to their work, the Nobel committee explained, "it is now possible to understand at the molecular level how the cell controls a number of central processes by breaking down certain proteins and not others. Examples of processes governed by ubiquitin-mediated protein degradation are cell division, DNA repair, quality control of newly-produced proteins, and important parts of the immune defense. When the degradation does not work correctly, we fall ill."

Shedding new light on the body’s failure to destroy certain tumor formations, the researchers' ubiquitin breakthrough has inspired a flood of follow-up activity in the world of science, with thousands of scholarly publications and hundreds of research groups around the world conducting related studies. The cancer drug Velcade, already in use, is based on the ubiquitin discoveries, and many other drugs that harness the protein-destroying process are in development.

2) Call Him ‘Mr. T’

How does the body fight cancer and other invaders? One key point man in the search for answers is Professor Yoram Reiter, head of the Laboratory of Molecular Immunology at the Faculty of Biology. He has developed two intriguing methods of waking up the immune system so it can identify and eliminate cancer dangers.

Professor Reiter
Professor Yoram Reiter

The immune system has two crucial defensive squadrons: T-cells, which are white blood cells that spot and neutralize diseases such as cancer or viruses within cells, and antibodies, which wipe out foreign molecules bound to cells but can't recognize when there is danger inside a cell. To Reiter, one solution seemed clear: combine the best abilities of both these defenders.

 

By genetically manipulating the antibodies, Reiter’s team was able to equip these proteins with T-cell-like receptors, thus adding the killing power of T-cells to the antibodies' superior skills in identifying a cancerous cell. Reiter has tested these new designer antibodies on melanoma, with promising results.

In working with T-cells, Reiter also knew that cells infected by a virus elicit a particularly effective immune response. This is due to the immunogenic peptides on their surface, which make them much easier to spot and destroy than cancerous cells. While the body is loaded with T-cells designed to battle marauding viruses such as influenza, it has relatively few cells that instinctively attack cancers.

So in a discovery hailed as “a significant new approach to immunology,” Reiter showed how to rouse the anti-viral T-cells for the fight against tumors. This time, what his team did was genetically engineer a molecule that attaches itself to cancer cells - and then signals the T-cells with a particular peptide that practically shouts, “Attack me!”

Reiter is testing this approach on several types of cancer, including ovarian, pancreatic and leukemia.

3) Cutting Off Cancer’s Lifeline

Tumors are living things that need nourishment to grow, so shutting down that lifeline could be another way to beat cancer.

Professor Vlodovsky
Professor Israel Vlodavsky

To gain nourishment, tumors secrete a substance that attracts blood vessels. Thanks to this process, called angiogenesis, the cancer can then infiltrate the blood and metastasize around the body. But Technion Professor Israel Vlodavsky has identified an enzyme called heparanase that is vital to both angiogenesis and metastasis - because it degrades the walls of blood vessels so that the tumor can invade the blood system.

Vlodavsky and his team are looking for something that will inhibit the enzyme. One promising candidate is the anti-coagulant heparin, and the research team has recently developed a chemically modified version to eliminate possible side effects such as bleeding.

Vlodavsky’s team received a five-year National Institutes of Health grant in 2004, and is recognized by NIH as the leading group working on the heparanase puzzle. Heparanase research has fast become a field of its own, and Vlodavsky is collaborating with experts worldwide.

More Key Advances

Ubiquitin, T-cells and heparanase are just three of the many compelling lines of anti-cancer inquiry under way at the Technion. The disease is being attacked from a variety of directions, often employing new tools such as stem cells or genetic engineering, or products as ancient as the humble pomegranate. Here is a summary of some current and recent work:

  • Detection: The American Cancer Society Web site includes the following statement “If you can't prevent cancer, the next best thing you can do to protect your health is to detect it early.” Dr. Hossam Haick of the Faculty of Chemical Engineering has developed a nanomaterial-based electronic "nose" that can detect various types of cancer tumors and determine the stage of the disease via breath samples.
  • Breaking Down Defenses: Cancer cells are devilishly clever in their ability to resist treatment. But Faculty of Biology Professor Yehudah Assaraf’s work is already leading to new drugs that clamp down on one important defense mechanism. He discovered that during chemotherapy, a mutation in the protein ABCG2 enables it to transport anti-cancer drugs out of the malignant cell, allowing the continued rapid spread of the disease. Assaraf and fellow researchers were able to delay the mutation from occurring, allowing the drugs to fulfill their mission. In a related project, Assaraf spotlighted the mutated protein’s role in helping breast cancer cells resist chemo by dumping the drugs into wastebasket-like structures.
  • A Current Event: Delivering a series of mild alternating fields of electricity via electrodes attached to the head, Professor Yoram Palti’s team has been able to double survival times for a small group of brain-tumor victims. Patients can receive the current continuously through a new device, the Novo-TTF, hooked to a small battery pack worn like a lightweight shoulder bag. Traditional radiation and chemotherapy target rapidly-dividing cancer cells, but the side effects can be debilitating because they destroy certain much-needed healthy cells that also happen to divide quickly. The experimental electrical therapy spares these good cells, and the TTF strategy (for Tumor-Treating Fields) also shows promise against breast, lung and other cancers. Palti's company, NovoCure Ltd., is enrolling patients for Phase III trials in the U.S. and Europe. For information, visit http://www.novocuretrial.com/.
  • The Human Touch: Many promising anti-cancer drugs look promising in animal tests, only to disappoint when research moves on to human trials. So in hopes of making animal testing more reliably predictive, Techion Professor Karl Skorecki has designed a process in which human embryonic stem cells are injected into mice to create teratomas, which are tumors made up of more than one type of human tissue. Made up of human tissues, these growths now allow scientists to better study cancer development, drug efficiency and side effects in a human environment.
  • Spittin’ Image: If you needed yet another reason to finally give up smoking, Technion research has dramatically illustrated how the chemicals in tobacco smoke destroy the protective substances in human saliva and combine with saliva to create a corrosive cancer-causing mix. Cigarette smoke “turns the body against itself" and leads normally beneficial saliva to become a “turn traitor,“ explains Dr. Raphael Nagler of the Faculty of Medicine, who hopes this research could point out new safeguards against oral cancer. He and Dr. Abraham Reznick have also studied how smoking turns vitamin C into a harmful oxidizing substance.
  • Solving a major puzzle in breast cancer studies, researchers led by Dr. Gera Neufeld pinpointed the specific protein that makes breast cancer cells invade other tissues. The LOR-1 protein (for lysyl-oxidase-related), causes tumors to spread and also induces the large amounts of collagen fibers that are a hallmark of deadly breast cancers. The team believes that chemicals to inhibit LOR-1 could be developed as possible treatments.
  • Pomegranates not only have powerful antioxidant properties, but the fruit could have important implications for breast cancer treatment and estrogen replacement therapy. Technion teams found that pomegranate seed oil triggers apoptosis - a self-destruct mechanism in breast cancer cells. Furthermore, pomegranate juice can be toxic to most estrogen-dependent breast cancer cells, while leaving normal breast cells largely unaffected.
  • Long-term use of L-thyroxin, the principal hormone secreted by the thyroid gland, reduces the risk of colorectal cancer by 50 percent, an international team of researchers including Technion experts has found. Another study on colorectal cancer showed that a genetic mutation often found in Ashkenazi Jews can triple its risk. Almost 2 percent of colon cancer patients studied were found to carry the mutation, compared to less than 1 percent of healthy volunteers tested as a comparison.
  • Women of childbearing age who must undergo chemotherapy are often left permanently infertile. But a Technion-designed hormone-blocking procedure, in which a patient's reproductive system is placed into a type of temporary "prepubescent stasis," protects patients’ ability to have children after chemotherapy ends.
  • Technion biologists’ success getting human embryonic stem cells to differentiate into the cells that make up blood vessels, and to actually form the vessels themselves, signals a major step forward in repair of the heart and other organs. But the knowledge could also help develop new cancer treatments. Because tumors must induce cells to become blood vessels in order to increase the tumor's own blood supply, the stem cell-derived cultures could show how to disrupt this process.

 

Cancer Research Who's Who

The world took notice in 2004, when Technion Professors Avram Hershko and Aaron Ciechanover won the Nobel Prize in Chemistry for uncovering the ubiquitin process by which damaged or unneeded proteins are marked for destruction to help keep the body healthy (see above).

Professor Hershko was born in Hungary in 1937 and came to Israel in 1950. He joined the Technion in 1972, and from 1987 has been a member of The Rappaport Family Institute. In 1998 he received the highest academic degree at the Technion, Research Professor. He has published more than 60 original papers and received honors such as the Lasker Award, Weizmann Prize for Sciences, the Israel Prize in Biochemistry and the General Motors Cancer Research Foundation Award. Prof. Hershko is examining the roles of ubiquitin-mediated protein degradation in the control of the cell division cycle. “We are focusing on the biochemical mechanisms involved in the degradation of two important cell cycle regulators: cyclin B, the major mitotic cyclin, and the CDK inhibitor p27, whose degradation is required for the transition of cells from quiescence to the proliferating stage.”

Professor Ciechanover was born in Haifa in 1947, and earned his Masters and Ph.D. at the Technion. Following post-doctoral training at M.I.T. in the early 1980s, he returned to the Technion and has been with the Faculty of Medicine ever since. Between 1994-2000 he served as director of The Rappaport Family Institute for Research in the Medical Sciences. He has published close to 100 original scientific papers on the ubiquitin system, and in 2008 was inducted as a foreign associate member of the National Academy of Sciences - one of the highest honors for scientists or engineers. He is currently the head of the Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering. He explains, “focuses on regulated activation and degradation of transcriptional regulators such as NF-κB - the major immune system modulator, p53 a key tumor suppressor, MyoD - the major transcriptional regulator involved in muscle differentiation, and p16 the cell cycle regulator.”

Profs. Hershko and Ciechanover are just two of the highly skilled and dedicated Technion experts in a wide range of disciplines who are closing in on the answers that will someday explain, prevent and cure cancer. Here are just a few of those worth watching:

Prof. Yoram Reiter, head of the Laboratory of Molecular Immunology at the Faculty of Biology, has received a $1 million grant from the U.S. National Institutes of Health a notable sum for a young researcher who is neither American nor U.S.-based. The ultimate goal of his immune-system research is an antibody-based drug that could be injected simply and quickly.

Prof. Israel Vlodavsky heads the David and Janet Polak Center for Cancer Research and Vascular Biology in the Faculty of Medicine. A professor of anatomy and cell biology, he is working on ways to short-circuit angiogenesis, the process by which tumors attract blood vessels and gain the nourishment they need to grow. He and his team have identified an enzyme called heparanase that is vital to both angiogenesis and metastasis, and are looking for something that will shut it down.

Prof. Yehudah Assaraf, of the Faculty of Biology, discovered how chemotherapy creates a mutation allowing a certain protein to divert anti-cancer drugs away from malignant cells, allowing the cancer to spread unchecked. He and his colleagues have learned how to delay the mutation from occurring and are hoping to design drugs with this effect.

Dr. Gera Neufeld, a professor of cell biology with the Faculty of Medicine, is deeply involved in projects seeking an inhibitor for the tumor-nourishing process of angiogenesis, and is examining the role the LOR-1 enzyme plays in breast cancer.

Dr. Tamar Kleinberger’s medical school laboratory is studying the induction of programmed cell death, or apoptosis, by the adenovirus E4orf4 protein. Finding that E4orf4 induces malignant cell-specific apoptosis, the microbiology professor feels the protein may point the way to new cancer-drug targets.

Dr. Amir Orian, a senior lecturer of anatomy and cell biology with the Faculty of Medicine, is looking at the network of genes that are involved in cell division and how to inhibit this cell division in cancer cells.

Dr. Dan Hershko, senior lecturer in surgery, is exploring mechanisms leading to increased expression of two ubiquitin ligase subunits - Skp2 and Cks1 - in breast cancer. He is hoping to track down the biological regulatory pathways responsible for these alterations, and design interventions to control the effects of these proteins.

Prof. Marcelle Machluf in the Laboratory for Cancer Drug Delivery at the Faculty of Biotechnology and Food Engineering is working on delivering specially-engineered growth-inhibiting cells directly to a tumor via a biodegradable nanocapsule.

Professor Karl Skorecki is current Director of the Rappaport Family Institute for Research in the Medical Sciences, as well as Director of Medical & Research Development. He directs the Molecular Medicine laboratory, where together with Dr. Sara Selig and Dr. Maty Tzukerman, he conducts research in varied areas of human molecular genetics and biology such as tumor formation.

Dr. Hossam Haick, senior lecturer in the Technion Department of Chemical Engineering and Russell Berrie Nanotechnology Institute, has developed a breath-based sensing device to detect cancer.  He has won recognition for this device including the Marie Curie Excellence Grant (the first Israeli researcher to do so), the 2008 Israel-France Foundation’s prestigious honor for promising scientists, and was named one of the world’s "100 Top Young Innovators" for 2008 by Technology Review magazine, MIT’s magazine of innovation. His article in the prestigious scientific journal Accounts of Chemical Research was the most accessed article in that journal in 2008. Dr. Haick grew up in Nazareth and attended St. Joseph’s School. He completed his undergraduate degree at Ben Gurion University and after completing his doctorate at the Technion. He went on to the California Institute of Technology for post-doctoral work, which earned him a Fulbright fellowship.

Facilities at the Forefront

The Technion medical school, the Rappaport Faculty of Medicine, has expanded steadily since its launch in 1969. The faculty includes world-class clinical scientists and clinical educators, about 350 technical and administrative personnel, more than 600 medical students and 200 graduate students.

As one of just a handful of medical schools around the world that are part of a technological institute, the Faculty can uniquely emphasize quantitative and basic sciences in training students to meet challenges of modern medical technologies. Collaborations between medicine are engineering are encouraged to develop new medical technologies that can treat cancer and other health problems of the 21st century.

Along with teaching and research, the mission of the Faculty of Medicine includes providing high-quality health care through a network of hospitals and clinics throughout northern Israel.

Within the Faculty of Medicine is the Rappaport Family Institute for Research in the Medical Sciences, established in 1982 to promote biomedical research. The Institute supports outstanding researchers from the Faculty of Medicine with funding, laboratory space and access to advanced equipment.

During more than two decades of activity, the Institute has established itself as an internationally recognized research center and counts among its members several world-renowned scientists.

A Cancer and Vascular Biology unit is one of several Centers of Excellence at the Technion, and current research groups there include “Regulation of Gene Expression, Development, Differentiation and Cancer” and “The Ubiquitin System and Cellular Protein Turnover.”

Another cancer-research hub is the Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering. Led by Technion Nobel Laureate Aaron Ciechanover, this center brings together the worlds of medicine, life sciences and engineering, providing state-of-the-art equipment and resources at the new J. Steven and Rita Emerson Life Sciences Building. 

The cadre of experts working here are focused on five research clusters:

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