Yale University Scientists Synthesize Long-Sought-After Anticancer Agent

A team of Yale University scientists has synthesized for the first time a chemical compound  called “lomaiviticin aglycon, ” which led to the development of a new class of molecules that appear to target and destroy cancer stem cells.

A team of Yale University scientists has synthesized for the first time a chemical compound called “lomaiviticin aglycon,” which led to the development of a new class of molecules that appear to target and destroy cancer stem cells.

Chemists worldwide have been interested in lomaiviticin’s potential anticancer properties since its discovery in 2001. But so far, they have been unable to obtain significant quantities of the compound, which is produced by a rare marine bacterium that cannot be easily coaxed into creating the molecule. For the past decade, different groups around the world have been trying instead to synthesize the natural compound in the lab, but without success.

Dr. Seth Herzon (center), along with team members Christina Woo and Liang Lu, synthesized a naturally occurring anticancer compound that scientists worldwide have been trying to replicate in the lab for nearly a decade.

Now a team at Yale, led by chemist Dr. Seth Herzon, has managed to create lomaiviticin aglycon for the first time, opening up new avenues of exploration into novel chemotherapies that could target cancer stem cells, thought to be the precursors to tumors in a number of different cancers including ovarian, brain, lung, prostate and leukemia. Their discovery appears online today in the Journal of the American Chemical Society.

“About three quarters of anticancer agents are derived from natural products, so there’s been lots of work in this area,” Herzon said. “But this compound is structurally very different from other natural products, which made it extremely difficult to synthesize in the lab.”

In addition to lomaiviticin aglycon, Herzon’s team also created smaller, similar molecules that have proven extremely effective in killing ovarian stem cells, said Gil Mor, M.D., Ph.D., a researcher at the Yale School of Medicine who is collaborating with Herzon to test the new class of molecules’ potential as a cancer therapeutic. This family of compounds are called “kinamycins.” The reactive core of the kinamycins also plays a key role in lomaiviticin aglycon, which is even more toxic and could prove even more effective in destroying cancer cells.

The scientists are particularly excited about lomaiviticin aglycon’s potential to kill ovarian cancer stem cells because the disease is notoriously resistant to paclitaxel (Taxol) and carboplatin, two of the most commonly used ovarian cancer chemotherapy drugs. “Ovarian cancer has a high rate of recurrence, and after using chemotherapy to fight the tumor the first time, you’re left with resistant tumor cells that tend to keep coming back,” Mor explained. “If you can kill the stem cells before they have the chance to form a tumor, the patient will have a much better chance of survival — and there aren’t many potential therapies out there that target cancer stem cells right now.”

Image of one of the kinamycin compounds synthesized by Yale researchers destroying ovarian cancer cells (the spherical objects) in less than 48 hours in lab tests. (Credit: Gil Mor)

Herzon’s team, which managed to synthesize the molecule in just 11 steps starting from basic chemical building blocks, has been working on the problem since 2008 and spent more than a year on just one step of the process involving the creation of a carbon-carbon bond. It was an achievement that many researchers deemed impossible, but while others tried to work around having to create that bond by using other techniques, the team’s persistence paid off.

“A lot of blood, sweat and tears went into creating that bond,” Herzon said. “After that, the rest of the process was relatively easy.”

Next, the team will continue to analyze the compound to better understand what’s happening to the stem cells at the molecular level. The team hopes to begin testing the compounds in animals shortly.

“This is a great example of the synergy between basic chemistry and the applied sciences,” Herzon said. “Our original goal of synthesizing this natural product has led us into entirely new directions that could have broad impacts in human medicine.”

Other authors of the paper include Liang Lu, Christina M. Woo and Shivajirao L. Gholap, all of Yale University.

Sources:

4 thoughts on “Yale University Scientists Synthesize Long-Sought-After Anticancer Agent

  1. So I’m a mutant – or at least, my tumors are. Explains a lot. Your reply was very helpful & I’ll check out OvCaRe. Exactly the type of terrific targeted information I referred to. Many thanks.

    Laura

    Like

    • Hi Laura,

      I am so sorry. I probably should have chosen my words more carefully. You certainly are not a mutant, although I might very well be! As for the information, you’re welcome.

      Best wishes,

      Paul

      Like

  2. Libby’s Hope website is exactly the type of cutting edge ovarian/cancer medical information I need. Ovarian cancer is under-researched, and my granulosa cell ovarian cancer is rare, so having a site that searches & posts targeted cancer news is incredibly useful. My hope and determination is to live long enough to benefit from these promising discoveries. Thank you for your good work & research!

    Like

    • Dear Laura,

      You’re welcome! We fully agree that ovarian cancer is under-researched, especially non-serous forms of epithelial ovarian cancer as well as non-epithelial forms of ovarian cancer. Granulosa cell and clear cell ovarian cancers are two of many relevant examples. We thank you for providing us with invaluable website feedback. The fact that you find the website helpful truly means a lot to us.

      For the benefit of our readers, granulosa cell ovarian cancer is a particular subtype of sex chord-stromal ovarian cancer. It occurs in approximately 1 out of every 100,000 women and accounts for less than 5% of all ovarian cancers. Coincidentally, we work closely with many members of the Ovarian Cancer Research Program of British Columbia (OvCaRe). OvCaRe discovered that 97% of all granulosa cell tumors possess an identical mutation in a gene called FOXL2, which results in the production of a mutant form of the FOXL2 protein. The FOXL2 protein has been shown by other research groups to be critical in the normal development of granulosa cells and it is also a “transcription factor.” Transcription factors are responsible for the regulation of other genes by turning them “on” or “off.” This is the first finding that has provided some insight into what might trigger the formation of granulosa tumors, and hopefully, will lead to the development of new therapies to target this rare subtype of ovarian cancer.

      Laura, with hope, determination, and further drug development, it is possible to “live to fight another day.” If we can assist you with medical research materials, please let us know and we’ll be glad to help.

      Keep the faith,

      Paul

      Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s