July 15, 2006, Updated September 12, 2012

Prof. Oded Shoseyov’s approach has been shown to inhibit the malignant cells without affecting normal cells and without the severe side effects of traditional treatments such as radiation and chemotherapy.There may not noticeably be a direct path from developing ways to grow larger peaches and nectarines to discovering a way to stop the growth and spread of cancer cells – but that hasn’t stopped Professor Oded Shoseyov.

The research team headed by Shoseyov at Hebrew University’s Faculty of Agriculture has used their knowledge and intuition of the inner workings of inhibiting cell growth to discover a protein that has the effect of blocking the blood supply to tumors.

Their approach has been shown to inhibit the malignant cells without affecting normal cells and without the severe side effects of traditional treatments such as radiation and chemotherapy. The strategy involves isolating the malignant tumor from its nutritional and oxygen supplies, thereby halting its growth and stopping metastases (spread of cancer cells to other parts of the body.)

“We were pretty much hoping and expecting to achieve the results we did, and we were pleased,” Shoseyov told ISRAEL21c. “But we realized that when we started investigating the mechanism, it was a fundamental process of nature, so we weren’t that surprised that we were proven right.”

The work on the project, which included Shoseyov’s associates Dr. Levava Roiz, Dr. Patricia Smirnoff and Dr. Betty Schwartz, was published recently in the journal Cancer of the American Cancer Society.

Shoseyov, an eighth generation Israeli who comes from a family of farmers, completed his PhD focusing on the biochemistry of wine flavor. His family’s vineyard in Carmey Yosef produces a boutique wine called Bravdo (bravdo.com), and it was his interest in agriculture that led him into his field of research.

“The goal of our initial research was to find solutions for farmer to increase the size of their peaches and nectarines. The problem is that the trees produce too many flowers – if you don’t perform manual thinning to reduce the flowers, you end up with a lot of fruit – but extremely small in size. Therefore they have less commercial value,” said Shoseyov.

“At the moment, the practice is to manually remove many of the fruitlets or flowers at the beginning of the season in the spring. However, it’s very labor intensive work. One worker can handle about 3-4 trees a day, and it’s a big effort. For example, if a hectare has 350 trees, it can take weeks and great expense to go through the whole orchard.”

Shoseyov and his team focused the actions of actibind, a protein that is produced by the black mold Aspergillus niger: a well-known microorganism used in bio and food technology. In plants, actibind binds actin, a major component of the intracellular structure in plants, interfering with the plants’ pollen tubes and halting cell growth.

“We studied this mechanism carefully and developed a process in which actibind was sprayed in the fields and reduced the number of flowers sprouting on the peach and nectarine trees,” he said.

An effort to commercialize the process failed because, in Shoseyov’s view, the fields had to be sprayed so many times, it was still more economically feasible to manually thin the trees. However, with disappointment came the silver lining – discovery.

“In the course of our work, we started to get deeper into the science and understand how the actibind inhibits growth. We surmised that this process of inhibiting tip growth is probably not exclusive to plants and fungi and is more of a natural phenomenon in nature and found in other organisms.

“Since cancer cells also have characteristic tip growth, we decided to check whether actibind has the ability to inhibit tip growth in cancer cells,” he said.

The team found an actibind-like protein, RNaseT2, was also subsequently found to bind actin in human and animal migrating cells, such as the cells that are responsible for new blood vessel formation (angiogenesis) in tumors.

“There are two important process in the development of a tumor,” explained Shoseyov -“metastases (spread of cancer cells to other parts of the body). Most cancer victims end up dying from a metatastic tumor, not a primary tumor, so preventing this metastases is extremely important.

“The second important process is angiogenesis – the development of blood vessels in the tumor which support its growth. If you’re able to prevent this – which also requires tip growth, you have another good mechanism to prevent tumor growth.”

The researchers discovered that by blocking the blood supply to the tumors, actibind halted the ability of malignant cells to move through the blood stream to form new metastases. A further plus is that actibind is not toxic to normal cells, thereby significantly minimizing the risk of side effects.

While Shoseyov may not have been surprised by the results, he admits that their research did provide an unexpected benefit.

During the completion of the human genome project, the gene encoding for RNaseT2, the human actibind-like protein which the HU researchers proved effective in inhibiting tumor growth, was found on chromosome 6.

“For many years, doctors have been using a certain molecular marker in humans to predict if a tumor is benign or malignant. When a patient has a tumor, a biopsy is taken and observed under a microscope. The rule of thumb is that if the tip of chromosome 6 is broken off, then it’s an indication that the tumor is malignant and the decision is taken to go full steam ahead with treatment like chemotherapy,” said Shoseyov.

As part of the human genome project, an Italian group asked ‘what missing at the end of this chromosome tip that enables the cells to become malignant when it’s broken?’ According to Shoseyov, the missing ingredient is… actibind.

“To our surprise, we found that actibind is also in humans. And when it’s not there, tip growth is not controlled, and that loss of control results in malignancy,” he said.

In laboratory experiments using cell cultures that originated from human colon cancer, breast cancer and melanoma, increasing the level of actibind was found to reduce the ability of these cells to form tumorogenic colonies. Further experimentation, with a variety of animal models, showed that the increased actibind inhibited the growth of colon cancer-derived tumors, metastases and blood vessel formation.

The fungal actibind and the human RNaseT2 represent the basis for a new class of drugs that could be used as a front-line therapy in the fight against cancer, say the researchers.

“Both in vitro and in vivo, we’ve shown that actibind has an anti-cancer effect.
We’ve file a patent that belongs to the university, and we’re now exploring the possibility of a further investigation in order to develop it into a cancer drug,” said Shoseyov.

While Shoseyov has no intentions of giving up his vineyard, the promising results of his study have convinced him to put aside his fruit research for the foreseeable future.

“It’s definitely going to be cancer from now on.”

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