Yeast platform enables production of anticancer agent in short supply
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Scientists from Denmark and the United States have engineered a yeast commonly used in foods to produce the precursor molecules for the anticancer agent vinblastine, a drug that has been in shortage several times in recent years.
“In 2019 and especially during the pandemic, we saw that vinblastine, together with its closely related analogue vincristine, were on FDA’s shortage drug list,” Jie Zhang, PhD, senior researcher at DTU Biosustain, told Healio. “Due to production delays and other reasons, the drug has been on the shortage list several times in the last 2 to 3 years. When we started the project in 2015, we didn’t know this shortage was going to happen.”
Zhang spoke with Healio about the groundbreaking work he and his colleagues conducted with engineered yeast. A study characterizing the work is published in Nature.
Healio: Why is vinblastine valuable in treating certain cancers?
Zhang: Vinblastine is a natural product that was discovered in the 1950s by scientists from Eli Lilly and University of Western Ontario, independently. It is derived from a plant called Catharanthus roseus and was one of the earliest chemotherapeutics approved by FDA. It has been listed on WHO’s essential medicines and widely used to treat various types of cancers, including some leukemias in children. When we started this project, we knew that vinblastine was one of the most complex small molecules and that its production relies exclusively on extraction from a plant. It takes about 500 kg, or a ton of dry leaves from the plant, and involves extracting the two precursors, called vindoline and catharanthine, and then using chemical coupling to make 1 g of vinblastine.
At the time we initiated this project, we thought it would be valuable to create a microbial production process using engineered yeast or other microorganisms to produce a sub-precursor in yeast fermentation, and then do chemical coupling so that we could produce the anticancer drug from renewable feedstocks like sugar and amino acids without using any plant material. That was the initial motivation. We didn’t know the shortages of vinblastine were coming, and we see that shortages will likely recur because of supply chain issues.
Healio: How did you engineer this yeast to produce vinblastine?
Zhang: We knew we could take genes from the plant and engineer them into yeast, like the yeast you use to brew beer or make bread. Yeast has been engineered for many different purposes, given that the biosynthetic pathway is already known. When we started in 2015, we didn’t know the full pathway for vinblastine. At that time, we only engineered part of the pathway to produce a precursor called strictosidine. The pathway for vinblastine has now been elucidated; the last two missing steps were discovered in 2018. That removed the last obstacle for making this molecule heterologously, because once we knew the pathway, we could engineer yeast to produce this molecule.
Healio: When will the vinblastine you synthesized become available to patients?
Zhang: There is still a long way to go before the technology can be commercialized for manufacturing. Compared with the current natural extraction process, the titer and productivity using our yeast strain are not economically viable. I think it will still take a few years to fully optimize the strain to make the process more efficient. Further, the fermentation process needs to be scaled up to lower the manufacturing cost. I believe our technology has paved the way, and it’s a matter of optimization and upscaling.
Healio: What is next in your research on this?
Zhang: There are many other potential therapeutics, including other anticancer, antimalaria, antihypertensive, antiaddiction and antipain agents, that we plan to evaluate. So, we are looking at the platform we just created to produce other, simpler molecules, making even higher value-added compounds. We are looking at some other molecules that have much bigger potential than vinblastine.
For more information:
Jie Zhang, PhD, can be reached at Kemitorvet Building 220, 2800 Kgs-Lyngby, Denmark; email: jzha@biosustain.dtu.dk.
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