
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.”
Back to topSeeking 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.”
Back to topComments
Vonnie Walls
Jul 28, 2014 • 2:16 PM
Geraldine E. Langdon
Jul 28, 2014 • 6:21 PM
Memorial Sloan Kettering
Jul 29, 2014 • 10:23 AM
In reply to Thank God for Sloan. You have by Geraldine E. Langdon
June Fay
Jul 28, 2014 • 9:25 PM
Justine
Jul 29, 2014 • 9:45 PM
Glenn Spielman
Aug 27, 2014 • 5:18 PM
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!
Elliot Tannenbaum
Aug 27, 2014 • 5:56 PM
Memorial Sloan Kettering
Aug 28, 2014 • 7:56 AM
In reply to The above article mentions by Elliot Tannenbaum
Brenda Zucchi
Aug 27, 2014 • 10:44 PM
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.
Carol Ossi
Aug 30, 2014 • 9:58 PM
Blancalilia R.Mohammed
Aug 30, 2014 • 10:19 PM
Memorial Sloan Kettering
Aug 31, 2014 • 10:09 AM
In reply to This is amazing discovery, I by Blancalilia R.Mohammed
Besaul
Sep 1, 2014 • 9:31 AM
ELLIOT TAUBMAN
Sep 5, 2014 • 4:02 AM
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.
Memorial Sloan Kettering
Sep 5, 2014 • 8:36 AM
In reply to AS AN MSKCC PATIENT FOR 14 by ELLIOT TAUBMAN
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.
Nuno Lemos
Nov 8, 2014 • 8:22 AM
Memorial Sloan Kettering
Nov 8, 2014 • 2:39 PM
In reply to will this drug be effective by nuno lemos
Nuno, both the compound discussed in this story and the early nanotechnologies discussed in some of our other blog posts are still at very early stages of development, and it’s too early to say which cancers they may be effective against. If you are interested in finding out what clinical trials we currently have available for adrenal carcinoma, you can call us at 800-525-2225 during regular business hours or go to http://www.mskcc.org/cancer-care/appointment for more information. Thank you for your comment.
Dione
Sep 20, 2015 • 9:42 AM
Dione, thank you for your question. This research is still in an early phase and the compound being explored is not yet in clinical trials. It is difficult to know at this stage when (or if) it will be tested in patients.
If you are interested in coming to Memorial Sloan Kettering for a consultation about metastatic melanoma, or in having your records reviewed, you can contact our International Center at 1-212-639-4900 or go to http://www.mskcc.org/cancercare/internationalpatients. The email address is international@mskcc.org.
Mohammed
Dec 25, 2016 • 3:44 AM
Dear Mohammed, we are unable to give treatment recommendations on our blog. If you would like to make an appointment with one of our specialists to discuss possible treatment options, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.
Marsha Ponce
May 13, 2019 • 5:12 AM
Memorial Sloan Kettering
May 13, 2019 • 9:17 AM
In reply to I have small cell adenoid… by Marsha Ponce
Dear Marsha, we’re sorry to hear about your diagnosis. This compound is still in very early stages of research and it’s too soon to know if it will ultimately be effective. If you’re interested in a consultation with an expert at MSK to find out what treatments are currently available, either as a part of standard care or a clinical trial, you can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to you.
Capable of destroying lymphoma.....I am interested in NHMCL and NHDLBCL.