From curse to cure: Turning a toxic fungus into a potential cancer treatment

Fungi gave us penicillin, and now they may have anticancer potential . After isolating a new class of molecules from Aspergillus flavus , a crop-toxic fungus linked to deaths in ancient grave excavations, Penn researchers modified the chemicals and tested them against leukemia cells. The result is a promising anticancer compound that rivals FDA-approved drugs and opens new frontiers in antifungal drug discovery.

"These results demonstrate that there are still many more natural product-derived medicines yet to be discovered," said Sherry Gao, Penn Compact Presidential Associate Professor of Chemical and Biomolecular Engineering (CBE) and Bioengineering (BE) and senior author of a new paper published in Nature Chemical Biology about the findings.

Aspergillus flavus, named for its yellow spores, has long been considered a harmful microbe. Following the opening of Pharaoh Tutankhamun's tomb in the 1920s, a series of untimely deaths among the excavation team fueled rumors of a pharaonic curse. Decades later, doctors theorized that fungal spores, dormant for millennia, may have played a role.

In the 1970s, a dozen scientists entered the tomb of Casimir IV in Poland . Within weeks, ten of them died. Further investigation revealed that the tomb contained A. flavus, whose toxins can cause lung infections, especially in people with weakened immune systems.

That same fungus is today the unlikely source of a promising new cancer therapy .

The therapy in question consists of a class of ribosomally synthesized peptides modified using the RiPPs procedure to enhance their anticancer properties. “Purifying these chemicals is difficult,” says Qiuyue Nie, a postdoctoral researcher at the CBE and first author of the paper. While thousands of RiPPs have been identified in bacteria, only a few have been found in fungi. This is due, in part, to previous researchers misidentifying fungal RiPPs as non-ribosomal peptides and to their limited understanding of how fungi create these molecules. “The synthesis of these compounds is complex. But that’s also what gives them their remarkable bioactivity,” she adds.

After purifying four different RiPPs, the researchers discovered that the molecules shared a unique interlocking ring structure. They named these previously unpublished molecules asperigimycins, after the fungus in which they were found.

Even without any modifications, when mixed with human cancer cells, the asperigimicins demonstrated medical potential: two of the four variants had potent effects against the leukemia cells .

Another variant, to which researchers added a lipid, or fatty molecule, also found in royal jelly that nourishes developing bees, worked as well as cytarabine and daunorubicin , two FDA-approved drugs that have been used for decades to treat leukemia.

To understand why lipids boosted the potency of asperigimycins, the researchers selectively turned genes on and off in the leukemia cells. One gene, SLC46A3, proved crucial in allowing asperigimycins to enter the leukemia cells in sufficient quantities.

That gene helps materials leave lysosomes, the tiny sacs that collect foreign materials entering human cells. “This gene acts like a gateway,” Nie says. “Not only does it facilitate the entry of asperigimycins into cells, but it may also allow other cyclic peptides to do the same.”

Like asperigimycins, these chemicals have medicinal properties (nearly two dozen cyclic peptides have received clinical approval since 2000 to treat diseases as varied as cancer and lupus), but many of them require modification to enter cells in sufficient quantities.

"Knowing that lipids can affect how this gene transports chemicals into cells gives us another tool for drug development," Nie says.

Through further experiments, the researchers discovered that asperigimycins likely disrupt the cell division process . "Cancer cells divide uncontrollably. These compounds block the formation of microtubules, which are essential for cell division," Gao says.

Notably, the compounds had little or no effect on breast, liver, or lung cancer cells (or on a variety of bacteria and fungi), suggesting that asperigimycins' disruptive effects are specific to certain cell types—a critical feature for any future drug.

In addition to demonstrating the medical potential of asperigimycins, the researchers identified similar gene clusters in other fungi, suggesting that more fungal RiPPS remain to be discovered . “Although only a few have been identified, almost all of them exhibit strong bioactivity. This is an unexplored region with enormous potential,” Nie says.

The next step is to test asperigimycins in animal models, with the hope of one day moving on to human clinical trials. “Nature has given us this incredible pharmacy. It’s up to us to uncover its secrets. As engineers, we’re excited to continue exploring, learning from nature, and using that knowledge to design better solutions,” says Gao.