A first-in-human Phase I trial has established preliminary safety and efficacy data for a reformulated version of thiostrepton, a mitochondrially targeted covalent PRX3 inhibitor, in patients with mesothelioma and other malignancies associated with malignant pleural effusion. The results were published in Nature Communications.
Thiostrepton was originally characterized decades ago and has since accumulated substantial preclinical evidence of anticancer activity, but its poor solubility and manufacturing complexity had previously precluded clinical development. The researchers undertook both the mechanistic characterization of the compound and the chemistry work required to bring it to a first-in-human setting.
“The goal was to take this drug called thiostrepton, which has been studied for 70 years, and formulate it in a way where it could be delivered to human beings for the first time ever, and use it as an anti-cancer drug,” explained principal investigator Brian Cuniff, PhD, associate professor at the University of Vermont.
Study population and design
Rather than restricting enrollment strictly to a single tumor histology, the trial enrolled patients on the basis of a shared clinical phenotype—malignant pleural effusion—which is most commonly, though not exclusively, associated with mesothelioma. This design allowed inclusion of a small subset of patients with metastatic lung and colorectal cancers alongside the mesothelioma-predominant cohort.
“Our primary goal is in the treatment of mesothelioma, but from a utilization and development standpoint, we’re very interested in testing it in other cancers,” Cuniff said.
Fifteen patients were enrolled, consistent with a dose-escalation, first-in-human design. “Around 30% of those patients we did see tumor reduction, and then we had 67% disease control,” Cuniff said, clarifying that disease control included patients whose “tumor didn’t grow for a period of time, or their tumor shrunk a little bit.”
A completed Phase II study is expected to provide a larger dataset on efficacy later this year.
Mechanistic rationale: PRX3 inhibition
The therapeutic rationale centers on thiostrepton’s activity as a covalent inhibitor of peroxiredoxin 3 (PRX3), a mitochondrial antioxidant protein. Preclinical work from Cuniff’s group established that irreversible PRX3 inhibition impairs mitochondrial bioenergetics and increases oxidative and metabolic stress selectively within tumor cells.
“It binds to the PRX3 protein irreversibly, and inactivates that protein, and that protein is really important for keeping the mitochondria of our cells… functioning correctly,” Cuniff said. “In tumor cells, we’re essentially taking away the ability for the tumor cell to make energy, and we’re also increasing waste products that are toxic to the tumor cells.”
A key element of the preclinical dataset is a reported therapeutic window between malignant and normal cell populations. “Our evidence shows that this same effect is not occurring in normal cells, and they can tolerate that inhibition much more than tumor cells,” Cuniff said.
Beyond direct cytotoxicity, investigators describe an additional immunomodulatory component to the drug’s activity, distinguishing it mechanistically from both chemotherapy and immune checkpoint-based approaches. “It’s not an immunotherapy, it’s not a chemotherapy,” Cuniff said. “It’s basically a cytotoxic immunomodulator. It kills cells, but it also has some activity against the immune system, which we think is important for its overall activity.”
Formulation and regulatory considerations
Historically, thiostrepton’s clinical translation was limited by poor aqueous solubility and manufacturing challenges. To address this, the development team formulated the compound into a micellar solution to enable solubilization and systemic delivery, and scaled manufacturing to meet regulatory-grade standards.
“We were able to manufacture the drug in a way that would allow it for the delivery to human beings, and then we developed a formulation that would allow for safe and effective delivery of the drug,” Cuniff said. The trial was conducted in the United Kingdom under MHRA oversight, the agency’s equivalent of the U.S. FDA.
Clinical context and unmet need
Cuniff situated the findings within a treatment landscape that has seen limited innovation. Standard-of-care chemotherapy for mesothelioma remained largely unchanged for roughly three decades until the 2021 approval of an immunotherapy-based frontline regimen—the most recent major regulatory advance for the disease.
“To only have two drugs essentially be approved in a 30-, 40-year period is unlike any other cancer,” Cuniff said, attributing the slow pace of development primarily to the disease’s rarity rather than to scientific tractability. “There’s not a ton of value in developing in mesothelioma because [of] the low patient population… although it really needs development. These patients, you know, they die very quickly. There’s not a lot of options, so we need new drugs.”
With Phase II data anticipated by year’s end, the investigators intend to further define thiostrepton’s efficacy profile in mesothelioma while continuing to evaluate its applicability across other PRX3-dependent tumor types.
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