This Lung Cancer Drug May Not Be What It Seems, Chemists Say

An experimental cancer drug may not work the way its manufacturer says it does , a new report claims. The drug, called antroquinonol, is currently being given to people with non-small-cell lung cancer who are enrolled in clinical trials taking place in the U.S. and Taiwan. It’s critically important to know what a drug’s active ingredient is, in order to manufacture it consistently and in order to make future improvements to it. So a study like this one, if it proves reproducible, is at best a wrinkle and at worst a roadblock on the path to a new FDA-approved lung cancer drug. This study is also another reminder of just how important chemistry is to making new medicines.

Antroquinonol comes from nature. Specifically, the Taiwan-based firm Golden Biotechnology Corporation purifies this molecule out from Antrodia camphorata, a mushroom used as a traditional Chinese herbal medicine. Over ten scientific publications describe the compound’s intriguing effects on cells in petri dishes or on small animals such as mice— anticancer activity, anti-inflammation activity, and anti-Alzheimer’s disease activity, to name a few.  Antroquinonol is currently in phase 2 clinical trials for the treatment of non-small-cell lung cancer, and the U.S. FDA has granted it orphan drug status (a kind of special fast-track status that includes other financial incentives) for treating pancreatic cancer and acute myeloid leukemia.

A story like that makes other scientists sit up and take notice. Enter Scripps Research Institute chemist (and MacArthur Genius Grantee) Phil Baran and pharmaceutical company Bristol-Myers Squibb (BMS). Wanting to study antroquinonol for themselves, they decided to take a different approach to production. Instead of starting from mushrooms and stripping everything else away, they decided to make antroquinonol from scratch. This is important for a few reasons. One is purity- it’s easier to be sure your sample is pristine when you’re building it yourself. Another is flexibility- if you’re smart about planning your blueprint to a molecule, you make it easy to produce related molecules. That can come in handy when you’re trying to ask scientific questions, as we’ll soon see.

Baran and BMS published their results in the open-access journal ACS Central Science. They aren’t the first to make antroquinonol A (the “A” is used to distinguish it from other molecules in its family). But they made over a gram of it. That may not sound like a lot, but it is more than other teams have made, and it is plenty for BMS biologists to test its effects.

Here’s where things get interesting— the BMS and Scripps scientists were not able to reproduce the prior results. They found that antroquinonol has minimal anti-tumor effects in cells and in mice. “I spent most of the next year trying to convince myself that I hadn’t screwed something up,” Matthew Villaume, a graduate student in Baran’s lab and the publication’s first author, writes. The BMS-Baran team then reasoned that perhaps antroquinonol could be breaking down to another molecule inside living things, and that that breakdown product is the active ingredient. So with the team’s chemical blueprint (remember I said that that was going to come in handy?) they made that most likely breakdown product. Unfortunately, it, too, had very little tumor-killing activity. Just in case, they also tested a molecule that is the mirror image of antroquinonol. Still no dice.

So what are the implications of this report? It could mean one of a few things. Either you need an extremely high dose of antroquinonol to have any effect, or antroquinonol isn’t the active ingredient behind all the intriguing results. If it’s not antroquinonol, perhaps it is an as-yet-unknown breakdown product, or perhaps it is another molecule from the mushroom that is present in small amounts after purification.

I shared this report with Miles Chih-Ming Chen, Golden Biotech’s head of clinical medicine. Chen says that slight differences in experimental conditions can lead to discrepancies in tumor-killing activity. Golden and its academic collaborators have carried out their own study of antroquinonol breakdown products in rats, where they turn up different, more extensively metabolized molecules. Chen also says that in phase 1 clinical trials of antroquinonol,  high daily doses (hundreds of milligrams) of the drug were deemed safe. The phase 1 trial is a small trial enrolling 13 patients in total.

Richard Feynman famously wrote, “What I cannot create, I do not understand.” And this is far from the first time chemists have stepped in to demystify a medication . In 2012, chemists determined that vendors were supplying a bogus version of leukemia drug bosutinib to researchers, potentially invalidating scores of scientific results. And in 2014, chemists pointed out that another anticancer drug in clinical trials, TIC10, wasn’t what its manufacturer claimed. “Now we see how ditching the chemistry can really bite you in the ass,” Scripps Research Institute chemist Kim Janda said at the time.

Golden Biotech’s treatment is currently in phase 2 clinical trials— this typically is the earliest test that’s designed to evaluate whether in fact a medication is efficacious in human patients. If the results are promising, it’s going to become all the more important to verify what is behind them.

Disclosure: I am a former employee of Chemical & Engineering News magazine, published by the American Chemical Society, which is also the publisher of ACS Central Science.