Plant found only in the Australian rainforest yields breakthrough cancer drug

[Feb. 4, 2023: Taylor Kubota, Stanford University]

The compound is found naturally in the seeds of the pink fruit of the blushwood tree, Fontainea picrosperma. (PHOTO CREDIT: Creative Commons)

Stanford University researchers have discovered a fast and sustainable way to synthesize a promising cancer-fighting compound in the lab. The compound’s availability was limited because its only currently known natural source is a single plant species that grows exclusively in a small region of rainforest in northeastern Australia.

Dubbed EBC-46 and technically called tigilanol tiglate, the compound works by promoting a localized immune response against tumors. The reaction ruptures the tumor’s blood vessels, eventually killing its cancer cells. EBC-46 recently entered human clinical trials after showing an extremely high success rate in treating a type of cancer in dogs.

However, due to its complex structure, EBC-46 did not appear to be synthetically accessible, meaning that no plausible route to practical laboratory manufacture appeared to exist. However, through an ingenious process, Stanford researchers have demonstrated for the first time how to chemically convert abundant plant source material into EBC-46.

As a bonus, this process can produce “analogues” of EBC-46 – compounds that are chemically similar but may prove even more effective and could potentially treat a surprisingly wide range of other serious diseases. These diseases, which include AIDS, multiple sclerosis and Alzheimer’s disease, all share biological pathways that are influenced by the target of EBC-46, a key enzyme called protein kinase C, or PKC.

similar posts

“We are very pleased to announce the first scalable synthesis of EBC-46,” said Paul Wender, Francis W. Bergstrom Professor in the School of Human Sciences, Professor of Chemistry and courtesy of Chemical and Systems Biology at Stanford, and corresponding author. of a study describing the findings in the journal Nature Chemistry. “The ability to produce EBC-46 in the lab really opens up tremendous research and clinical opportunities.”

The study’s co-authors are Zachary Gentry, David Fanelli, Owen McAteer and Edward Njoo, all graduate students in Wender’s lab, as well as former member Quang Luu-Nguyen.

Wender conveyed the research team’s immense satisfaction with the breakthrough in the synthesis of EBC-46. “If you had visited the lab in the first weeks after their success,” Wender said, “you would have seen my exceptional colleagues smiling from ear to ear. They managed to do what many people thought was impossible.

Doctoral students Edward Njoo, David Fanelli, Zach Gentry and Owen McAteer. These researchers succeeded in synthesizing the anti-cancer compound EBC-46. (Image credit: Paul Wender)

From a distant region

Tigilanol tiglate originally appeared in an automated drug candidate screening process by Australian company QBiotics. The compound is found naturally in the seeds of the pink fruit of the blushwood tree, Fontainea picrosperma. Marsupials like musk-kangaroos that eat blushwood fruits avoid the seeds rich in tigilanol tiglate, which ingesting them causes vomiting and diarrhea.

Injection of much lower doses of EBC-46 directly into some solid tumors alters cell signaling by PKC. Specifically, EBC-46 is thought to activate certain forms of PKC, which in turn affect the activity of various proteins in cancer cells and trigger an immune response from the host body.

Paul Wender, Professor Francis W. Bergstrom at the Faculty of Humanities, Professor of Chemistry. (Image credit: Paul Wender)

The resulting inflammation leaks the vasculature or blood vessels of the tumor, and this bleeding causes the tumor growth to die. In external cutaneous malignancies, the tumors crust over and fall off, and ways to deliver EBC-46 to internal tumors are being explored.

In 2020, the European Medicines Agency and the United States Food and Drug Administration approved a drug based on EBC-46 sold under the brand name Stelfonta for the treatment of mast cell cancer, the most common skin tumor. common in dogs.

One study showed a 75% cure rate after a single injection and an 88% cure rate after a second dose. Clinical trials have since begun for skin, head and neck, and soft tissue cancers in humans.

Based on these emerging research and clinical needs, coupled with the geographical limitations of parental seeds, scientists considered establishing dedicated plantations of blushwood trees. But this poses a multitude of problems.

For starters, trees need to be pollinated, which means having the right kind of pollinating animals available, as well as planting trees at the correct density and spacing to support pollination. In addition, seasonal and climatic fluctuations as well as pathogens affect the trees. The abandonment of plots for blushwood trees poses other land use problems.

“For sustainable and reliable production of EBC-46 in the quantities we need,” Wender said, “we really need to go the synthetic route.”

Make EBC-46 from scratch

A good starting point for making EBC-46, Wender and his colleagues recognized, is the plant-derived compound phorbol. Over 7,000 plant species worldwide produce phorbol derivatives, and phorbol-rich seeds are commercially inexpensive. The researchers chose Croton tiglium, commonly known as purifying croton, an herb used in traditional Chinese medicine.

The first step in the preparation of EBC-46, explains Wender, is based on daily experience. “You buy a bag of these seeds, and it’s no different from making coffee in the morning,” Wender said. “They grind the seeds and run a hot solvent through them to extract the active ingredient,” in this case a phorbol-rich oil.

After turning the oil into phorbol, the researchers had to find a way to overcome the previously insurmountable challenge of capping a part of the molecule, called the B ring, with carefully placed oxygen atoms. This is necessary for EBC-46 to interact with PKC and alter the activity of the enzyme in cells.

To guide their chemical and biological studies, the researchers relied on instruments from the Stanford Neuroscience Microscopy Service, the Stanford Cancer Institute Proteomics/Mass Spectrometry Shared Resource, and the Stanford Sherlock Cluster for computational modeling.

Using these tips, the team succeeded in adding additional oxygen atoms to the B ring of phorbol, initially via what is called an ene (pronounced “een”) reaction, which is carried out under conditions of flow, the reactants mixing as they pass through the tubes together running. The team then introduced additional cyclic B groups in a gradual and controlled manner to achieve the desired spatial arrangement of the atoms. In all, only four to six steps were required to obtain EBC-46 analogs and a dozen steps to achieve EBC-46 itself.

Tigilanol tiglate is a natural diterpenoid in clinical trials for the treatment of a wide range of cancers. (CREDIT: Stanford University)

Wender hopes that the much wider availability of EBC-46 and its PKC-affecting cousin compounds made possible by this breakthrough approach will accelerate the search for potentially breakthrough new treatments.

“As we learn more about how cells work, we learn more about how we can control that functionality,” Wender said. “This control of functionality is particularly important when dealing with cells that go rogue in diseases ranging from cancer to Alzheimer’s disease.”

Wender is also a Fellow of Stanford Bio-X and the Stanford Cancer Institute and a member of Sarafan ChEM-H.

For more scientific news, visit our New Innovations section on The lighter side of the news.

Note: The documents provided above are from Stanford University. Content may be edited for style and length.

Do you like these kind of feel-good stories? get that Brighter Side of News Newsletter.


#Plant #Australian #rainforest #yields #breakthrough #cancer #drug

Breakthrough device uses ultrasonic ‘tornado’ to break up blood clots

[Feb. 3, 2023: Matt Shipman, NC State University]

The schematic representation of the sonothrombolysis process using a vortex ultrasound transducer. The Vortex Ultrasound Transducer is built into a 9 Fr catheter and inserted into the blood vessel with a blood clot. (PHOTO CREDIT: Research Magazine)

Researchers have developed a new tool and technique that uses “vortex ultrasound” – a type of ultrasonic tornado – to break up blood clots in the brain. The new approach worked faster than existing techniques to eliminate clots that had formed in an in vitro model of cerebral venous sinus thrombosis (CVST).

“Our previous work looked at various techniques that use ultrasound to clear blood clots with essentially forward waves,” says Xiaoning Jiang, a co-author of a paper on the work. “Our new work uses vortex ultrasound, where the ultrasonic waves have a spiral wavefront.

“In other words, the ultrasound swirls as it moves forward,” says Jiang, who is the Dean F. Duncan Professor of Mechanical and Aerospace Engineering at North Carolina State University. “Based on our in vitro testing, this approach clears blood clots faster than existing techniques, primarily due to the shear stress induced by the vortex wave.”

“The fact that our new technique works quickly is important because CVST clots increase pressure on blood vessels in the brain,” says Chengzhi Shi, co-author of the paper and an assistant professor of mechanical engineering at Georgia Tech. “This increases the risk of cerebral hemorrhage, which can be catastrophic for patients.

Similar news

“Existing techniques are largely based on interventions that dissolve the blood clot. However, this is a time-consuming process. Our approach has the potential to target these clots faster and reduce risk for patients.”

CVST occurs when a blood clot forms in the veins that are responsible for draining blood from the brain. Incidence rates of CVST ranged from 2 to 3 per 100,000 in the United States in 2018 and 2019, and the incidence rate appears to be increasing.

“Another reason why our work here is important is that current treatments for CVST fail 20-40% of the time,” says Jiang.

The new tool consists of a single transducer specifically designed to create the swirling vortex effect. The transducer is small enough to be incorporated into a catheter, which is then passed through the circulatory system to the site of the blood clot.

High-velocity endovascular sonothrombolysis with vortex ultrasound-induced shear stress. a, The schematic view of the sonothrombolysis process using a vortex ultrasonic transducer. The Vortex Ultrasound Transducer is built into a 9 Fr catheter and inserted into the blood vessel with a blood clot. (PHOTO CREDIT: Research Magazine)

For proof-of-concept in vitro testing, researchers used cow blood in a 3D-printed model of the cerebral venous sinus.

“Based on available data, pharmaceutical procedures to dissolve CVST blood clots take at least 15 hours and average about 29 hours,” says Shi. “In in vitro tests, we were able to dissolve an acute blood clot in well under half an hour.”

Comparison of in vitro thrombolytic treatment outcomes for non-vortex and vortex ultrasonic transducer treatments. a, 30 minute treatment compared to the same level of puncture force. The horizontal white dashed lines mark the current position of the ultrasonic transducer. (PHOTO CREDIT: Research Magazine)

With any catheterization or surgical procedure, there is a potential risk of injury, such as B. damage to the blood vessel itself. To address this problem, the researchers conducted experiments using vortex ultrasound on animal blood vein samples. These tests revealed no damage to the walls of the blood vessels.

The researchers also ran tests to determine whether the vortex ultrasound caused significant damage to red blood cells. They found that the red blood cells were not significantly damaged.

The 3D phantom study of in vitrosonothrombolysis with vortex ultrasound transducer treatment.a, Diagram of the 3D phantom model of the cerebral venous sinus with blood vessels labeled and the location of the blood clot passing along the superior sagittal sinus into the transverse sinus. (PHOTO CREDIT: Research Magazine)

“The next step is that we conduct tests with an animal model to better demonstrate the feasibility of this technique for CVST treatment,” says Jiang. “If these tests are successful, we hope to be able to conduct clinical trials.”

“And if vortex ultrasound ever becomes a clinical application, the cost would likely be comparable to other interventions used to treat CVST,” Shi says.

The publication, A Model of High-Speed ​​Endovascular Sonothrombolysis with Vortex Ultrasound-Induced Shear Stress to Treat Cerebral Venous Sinus Thrombosis, is published in the open-access journal Research, a Science Partner Journal. The paper’s co-lead authors are Bohua Zhang, a Ph.D. student at NC State; Huaiyu Wu, a postdoctoral fellow at NC State; and Howuk Kim, a former Ph.D. Student at NC State now teaching at Inha University.

The paper was co-authored by: Georgia Tech’s Phoebe Welch; Ashley Cornett, Greyson Stocker, Gabe Owens, and Zhen Xu from the University of Michigan; Raul Nogueira of the University of Pittsburgh Medical Center; Jinwook Kim, research assistant professor in the Joint Department of Biomedical Engineering at North Carolina State University and the University of North Carolina, Chapel Hill; and Paul Dayton, department head and William R. Kenan Distinguished Professor in the Joint Department of Biomedical Engineering.

For more science and technology stories, check out our New Discoveries section at The lighter side of the news.

Note: Materials provided above from NC State University. Content can be edited for style and length.

Do you like these kinds of feel-good stories? get that Brighter Side of News newsletter.


#Breakthrough #device #ultrasonic #tornado #break #blood #clots