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Victory in Numbers

23.02.2015

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We tend to think of cancer as a single disease, but in fact, there are dozens of different cancers, each caused by a specific set of genetic defects. An international team headed by Weizmann Institute researchers has identified a previously unknown defect that occurs in certain breast cancer patients. Under license from Yeda Research and Deveolpment Co., the Weizmann Institute’s technology transfer arm, the pharmaceutical company Merck Serono has started developing a drug that in the future may help prevent metastasis – the spread of the cancer to other organs – in patients with this genetic aberration.

Defects of the type discovered in the new study stem from chromosome abnormalities that in some cases create extra copies of certain genes beyond the two normally present in each cell of the body. One such abnormally multiplied gene, most commonly known as HER2, was discovered more than two decades ago and has already become a target for a drug, Herceptin®, which successfully treats a certain proportion of breast cancer patients with too many HER2 copies.
 
(l-r) Prof. Marcelo Ehrlich, Dr. Silvia Carvalho, Dr. Haim Barr, Prof. Yosef Yarden and Dr. Nir Ben-Chetrit
 

 

 
In the new study, reported in Science Signaling, an international team of researchers headed by Prof. Yosef Yarden of the Weizmann Institute of Science, performed a computerized analysis of some 2,000 genomes of breast cancer patients. Their investigation turned up yet another gene, SYNJ2, which is present in too many copies in a certain number of breast cancers. The study was conducted in the Weizmann Institute’s Biological Regulation Department by Yarden’s graduate student Nir Ben-Chetrit, in collaboration with Yarden’s team member Dr. Silvia Carvalho, Profs. Tsvee Lapidot and Ronen Alon of Weizmann’s Immunology Department, Dr. Haim Barr of the Nancy & Stephen Grand Israel National Center for Personalized Medicine (G-INCPM) and Prof. Marcelo Ehrlich of Tel Aviv University, as well as other scientists and students from Israel and abroad.

The study revealed that women with extra copies of the SYNJ2 gene died sooner than the average for breast cancer patients in the sample, suggesting that excessive copies of this gene could be deadly. The function performed by SYNJ2 in the cell also points to its potential role in decreasing survival: It facilitates the migration of cells – a sometimes useful task, but one that also enables metastasis, the major cause of death from cancer. The SYNJ2 gene encodes an enzyme that operates on the side of the cell facing the direction of movement; this enzyme helps the cell to form extensions called podia that are essential for its migration, as well as enlisting other enzymes that drill a path through walls of arteries and veins, enabling the cancer cells to stream throughout the body.
 
A metastatic breast cancer cell under a fluorescent microscope. The SYNJ2 gene marks “signposts” for two substances (top left, green and red dots), which then enable the cell to drill holes (top right, black dots) in the extracellular matrix, in preparation for metastasis; when SYNJ2’s function is disrupted, one of these substances fails to get recruited and diffuses instead throughout the cell (bottom left, green fluorescence), so there are no signposts (bottom right) and thus the cell cannot drill into the matrix
 

 

When the scientists disabled SYNJ2 in breast cancer cells in a laboratory dish using genetic engineering, the cells’ movement was impeded because they failed to form podia. The researchers then implanted mice with different types of breast cancer cells – those that had a functioning copy of the SYNJ2 gene and those that did not. The cells with the functioning SYNJ2 produced faster-growing tumors and caused more metastases to the lymph nodes and lungs than the ones without the copy.

The next step was to find a prototype for a drug that could be applicable to human patients. With the help of advanced screening technology available at the G-INCPM, the researchers sifted through tens of thousands of small molecules, ultimately identifying one that effectively blocked SYNJ2’s activity. Moreover, it worked with a great deal of precision, targeting SYNJ2 without affecting sibling enzymes, suggesting that it would cause no major unwanted side effects.

This potential therapy, under consideration for further development by Merck Serono, will be aimed at women whose breast tumors have extra copies of SYNJ2 – about four percent of all breast cancer patients. This number may not sound like much, but considering that nearly 1.7 million new breast cancer cases are diagnosed around the world each year, over time the ability to treat this particular type might translate into millions of saved lives.
 

 
Prof. Ronen Alon’s research is supported by the M.D. Moross Institute for Cancer Research; Lord David Alliance, CBE; and Mr. and Mrs. William Glied, Canada. Prof. Alon is the incumbent of the Linda Jacobs Professorial Chair in Immune and Stem Cell Research.

Prof. Tsvee Lapidot’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research, which he heads; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; and the Dr. Beth Rom-Rymer Stem Cell Research Fund. Prof. Lapidot is the incumbent of the Edith Arnoff Stein Professorial Chair in Stem Cell Research.

Prof. Yosef Yarden’s research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Maurice and Vivienne Wohl Biology Endowment; the Louis and Fannie Tolz Collaborative Research Project; the European Research Council; and the Marvin Tanner Laboratory for Research on Cancer. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.


 
 
 
 

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