In the Lab

On Cancer: Compound from Tropical Plant Targets Key Cancer-Causing Genes

An origami crane illustrates the importance of RNA folding for regulating gene translation. The bolded sequences on the crane’s wings indicate the portion that is critical for the manufacture of many cancer-causing proteins. An origami crane illustrates the importance of RNA folding for regulating gene translation. The bolded sequences on the crane’s wings indicate the portion that is critical for the manufacture of many cancer-causing proteins.

Many of the most effective cancer therapies available today have been developed by determining which genes lead cells to become cancerous and figuring out how to block the activity of those genes with drugs. But scientists have not yet been able to find a drug to inhibit MYC, one of the first cancer-causing genes discovered and one of the most well studied.

Now Memorial Sloan Kettering investigators Andrew Wolfe and Kamini Singh and their colleagues have looked to nature and found a compound that blocks a cell’s ability to produce the “undruggable” MYC protein. In the laboratory, the compound is proving capable of destroying leukemia and lymphoma cells and even some solid tumors. Treatment with an effective dose of the drug was well tolerated in animal models.

“For as long as we’ve known about MYC — about 40 years — we’ve looked for a way to block it,” says Memorial Sloan Kettering cancer biologist Hans-Guido Wendel, the senior author of the study, which was published online yesterday in Nature. “MYC is clearly important for many different cancers, however, efforts in academia and in industry to target MYC have not been successful. Instead of targeting the MYC protein, we now have a drug that completely prevents its production — and this proves to be a highly effective alternative.”

A New Method

The compound, called Silvestrol, does not work through the mechanisms used by most targeted therapies. “Many other drugs work by targeting kinases, proteins that are important in cell signaling and the regulation of other proteins,” Dr. Wendel says.

Silvestrol works by targeting an RNA helicase, a type of protein that regulates genes by changing the structure of their RNA. Without this RNA helicase, cells are unable to translate the MYC gene into the MYC protein, preventing the cancer-inducing activity of the gene.

“With help from the team of Gunnar Rätsch, who developed new computational tools, we dug a little deeper into how Silvestrol works and found that it is effective against a group of proteins made by messenger RNAs that often share a structure, or molecular shape, called a G-quadruplex,” says Dr. Singh, a postdoctoral fellow in Dr. Wendel’s lab and one of the paper’s two first authors. “This structure is found in many other cancer-causing genes, or oncogenes, which means that Silvestrol is able to inhibit other important oncogenes in addition to MYC.”

“Cancer cells are dependent on the proteins encoded by these oncogenes,” adds Dr. Wolfe, a former fellow in Dr. Wendel’s lab and the other first author, who is now a postdoctoral fellow at Mount Sinai. “Removing them causes the cells to undergo apoptosis and die.”

Seeking Cancer Drugs in Nature

Silvestrol is a natural product found in a plant called Aglaia foveolata, which is native to Indonesia, Brunei, and Malaysia. Although, “nobody knows — it might also grow in Central Park or many other places,” Dr. Wendel says.

The effort to develop drugs from natural products is based on the idea that these molecules have an inherent biological function that can be enhanced and exploited. Many of the most successful cancer drugs to date have been based on natural products, including paclitaxel (Taxol®), which was isolated from the Pacific yew tree, and vincristine, which comes from the Madagascar periwinkle.

Earlier research by McGill University biochemist Jerry Pelletier, a collaborator on the study, had indicated that Silvestrol can block protein translation in cancer cells. But because the compound could be extracted from the plant only in very small quantities, the research team also looked at analogs of Silvestrol that could be manufactured in a laboratory. Analogs are chemical compounds with a structure that is slightly altered from another compound but often have the same or a very similar chemical function.

“We’ve already found a highly effective analog of Silvestrol that works very well,” Dr. Wendel says. “However, to take this drug to the clinic will require significant funding and additional chemistry work.” He is hoping to find both at Memorial Sloan Kettering.

The next step is to continue testing Silvestrol and its analogs against leukemia as well as other types of tumors. The researchers emphasize that more study is needed to determine the most effective dose as well as any side effects that may occur before clinical trials can begin in patients.

“Blocking the production of key cancer genes is a completely new way of treating cancer,” Dr. Wendel concludes. “That is exciting, and it also means we have a lot to learn about it.”

Funding information: This research was supported by the National Cancer Institute under grant number R01-CA142798-01, the Leukemia Research Foundation, the Experimental Therapeutics Center at MSK, and the American Cancer Society. Dr. Wendel is also a Scholar of the Leukemia & Lymphoma Society.

Comments

Capable of destroying lymphoma.....I am interested in NHMCL and NHDLBCL.

Thank God for Sloan. You have helped my Son, Donnie, live. I am ever grateful for your dedication to fine a cure. Everyone is so kind and treats your patients and family as if they we were the only persons you are treating. You are all in my prayers. Thank you.

Thanks so much for sharing your story, Geraldine.

Interesting article concerning the several naturally occurring plant substances that exist in the "organic world". I was a recipient of Vincristine, part of the CHOP regimen, during my treatment for NHL in 2002, in combination with an autologous transplant . June Fay

This is amazing. How long until clinical trials on human patients? This seems promising.

Dear Justine, thanks so much for your comment. The research is still very early, so we can't make any projections about clinical trials just yet.

As Dr. Wendel states, "Blocking the production of key cancer genes is a completely new way of treating cancer ... ”. It would appear that this can become better than a cure as it should function as a preventative to acquiring the cancer(s). People would not have to suffer the indignities of the disease to be "cured"; they won't get it in the first place. As a man who lives with metastatic, advanced cancer, this may be a very significant breakthrough for so many! Am also a patient at MSK; Thank you!

The above article mentions that the Silvestrol was successful in use against some solid tumors. Did these tumors include primary brain tumors?

Elliot, according to Dr. Wendel, Silvestrol has not yet been tested against brain tumors, but they plan to look at that in the laboratory soon. Thank you for your comment.

Could this be used on mestastic rectal cancer to the lung. Am also a patient at MSK

Brenda, we sent your question to Dr. Wendel, who responded, "We are in the process of testing silvestrol against about 70 human cancer types. This will take several months. Ultimately, moving the drug into the clinic will take two to three years and $2 million to $5 million. At this point we have secured $200,000 in funding for the next two years." Thank you for your comment.

As a retired R.N. & a Breast Cancer survivor thanks to MSK, I am very interested in following this new development. It is so logical to attack cancer in this way. I know you will be successful in this endeavor. God bless you & this important work.

This is amazing discovery, I am very happy that it is hope for so many people. I wonder if this can be apply to breast cancer.
Thank you for existing and for your perseveration and for sharing such as discoveries.

Blancalilia, this treatment is still in the very beginning stages of study and it is too early to say which cancers it may be effective against. Thank you for your comment.

Julie Grisham's simple explanation of the MYC Gene and how cancer cells proliferate and can be halted makes for easy reading. This article was very educational. Thanks to all of the hard working selfless Scientists and Oncologists at MSK. May your research be very successful.

AS AN MSKCC PATIENT FOR 14 YEARS, PRESENTLY IN REMISSION, I KNOW WHAT YOU CAN DO. AS AN ATTORNEY, I HAVE ALSO OBTAINED FUNDING FOR EXPERIMENTAL WORK AT MSKCC. SINCE ONE OF THE PROMISING AREAS IS LEUKEMIA, HOW CAN I GET A CLIENT INTO AN EXPERIMENTAL PROGRAM? HE HAS BEEN TREATED, UP THE RIVER IN WESTCHESTER, FOR HIS "INCURABLE" BUT "TREATABLE" LEUKEMIA. HE IS IN BASIC GOOD HEALTH AND SPENT HIS CARRIER AS A RESEARCH CHEMIST, BUT IS NOW RETIRED. PLEASE ADVISE.

Elliot, thank you for reaching out. If your client would like to make an appointment with a Memorial Sloan Kettering physician, he can call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. They will be able to provide information about any clinical trials that may be appropriate. Thanks for your comment.

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