How a Seagen cancer drug with Nobel Prize science might also work in diabetes

Some diabetes therapies work by ramping up the body’s secretion of insulin to counteract high blood sugar levels. But a team of scientists at the Karolinska Institute believe preserving insulin-producing pancreatic beta cells—rather than overloading them—would be a better diabetes treatment strategy over the long term.

Following that thinking, the team showed that an experimental cancer drug made by Seagen dubbed PX-478 could improve the function of beta cells and restore blood sugar balance in diabetic mice. The results are published in the journal Science Translational Medicine.

Because PX-478 has already been tested in a clinical trial as an anti-cancer drug and was well tolerated in these patients, the Karolinska researchers hope they could quickly move the drug into clinical trials of diabetes after additional animal tests.

PX-478 is an inhibitor of the hypoxia-inducible factor 1-alpha (HIF-1alpha) protein. The 2019 Nobel Prize in physiology or medicine went to three scientists for their discoveries of HIF’s role in how cells respond to low oxygen levels, or hypoxia.

In Type 2 diabetes, continuous insulin resistance sends pancreatic beta cells into overdrive as the cells try to maintain normal blood sugar levels, eventually wearing the cells out. Previous studies have linked the metabolic dysfunction with hypoxia and HIF-1alpha, given the high energy, oxygen-dependent demands of insulin secretion.

Under normal circumstances, HIF-1alpha is quickly degraded. But in diabetic mouse models, HIF-1alpha was stabilized and accumulated in the animals’ pancreatic islets amid hypoxia caused by an increase in metabolic workload, the Karolinska team found.

The researchers treated the diabetic mice with PX-478. In a mouse model of “extreme” Type 2 diabetes marked by early loss of beta cell function, PX-478 prevented the rise of blood glucose. Mice treated with the drug kept plasma insulin concentration elevated, suggesting their beta cells were still working to release insulin to compensate for insulin resistance. By contrast, untreated mice saw their insulin concentration drop.

In another mouse model with reduced functional beta cells, PX-478 treatment brought blood sugar levels under control, whereas hyperglycemia persisted in nontreated mice.

Pancreatic islets isolated from PX-478-treated mice showed hallmarks of improved beta cell function including an increase in insulin content and expression of genes involved in beta cell function and maturity as well as the formation of insulin granules similar to those of nondiabetic control mice.

The drug also showed similar benefits in organoids of human pancreatic cell islets. It cooled the human beta cells down by reducing basal insulin secretion and increasing a response to high blood sugar, the researchers found.

Hypoxia has broad implications in various diseases. And this is not the first time that scientists have found the repurposing potential of PX-478 in a disease beyond cancer. A research team at Yale University previously discovered that PX-478 held promise for lupus nephritis, because it could reduce kidney inflammation from kidney-infiltrating T cells. 

Because insulin production declines during diabetes, therapeutic strategies have so far mainly focused on improving beta cells' insulin production. Other research efforts that have also focused on the preservation of beta cell function, including targeting the protein TXNIP by scientists at the University of Alabama at Birmingham.

“Current therapies targeting beta cells have only a temporary positive effect on insulin secretion,” Per-Olof Berggren, the current study’s co-senior author, said in a statement. “In the long-term, these drugs lead to beta-cell exhaustion.”

Next up, the Karolinska team aims to test PX-478’s effect on human pancreatic beta cell function in a “humanized” mouse model in which immunosuppressed mouse is transplanted with human islets.