Pancreatic cancer, one of the most lethal human cancers, is known for it its lack of blood vessels, which creates an environment of low oxygen, or "hypoxia." While studying how pancreatic tumors adapt to hypoxic stress, scientists at Sanford Burnham Prebys Medical Discovery Institute pinpointed a protein that appeared to be driving metastasis.
Removing the protein, called PPP1R1B, in mice significantly reduced pancreatic cancer’s ability to spread to the lung and prolonged the animals’ lives, the team reported in the journal Gastroenterology.
Based on the results, the researchers argued that PPP1R1B could be a novel drug target, and that inhibiting it could help treat pancreatic cancer.
In response to hypoxia, cells usually activate the hypoxia-inducible factor (HIF) family of transcription factors. Increased expression of H1F1A is often linked with poor patient outcomes in some cancer types, including breast and colorectal cancers.
The Sanford Burnham Prebys researchers suspected that the same correlation would hold true in pancreatic cancer. But to their surprise, mice genetically modified to lack H1F1A instead had more aggressive pancreatic cancer and lived much shorter than control animals did. These H1F1A-negative mice also showed evidence of increased local invasion into nearby tissues, as well as metastasis to distant organs.
To understand what was driving the cancer cells’ invasiveness, the team screened for proteins that acted differently in the two types of mice. One protein stood out: PPP1R1B. Increased levels of PPP1R1B have been reported in several cancers and associated with poor prognosis, but its role in pancreatic cancer wasn’t clear.
By studying several human pancreatic cancer cell lines, the researchers also found that decreased H1F1A was correlated with increased PPP1RB and high metastatic growth.
The scientists then removed PPP1R1B in pancreatic cancer cells and injected them into mice. PPP1R1B depletion led to significantly reduced lung metastasis as compared with animals that got unaltered cells, the team reported. Further analysis revealed that the protein promoted metastasis in pancreatic cancer by reducing p53, which is a well-characterized regulator of cell division and a key tumor suppressor protein.
The 2019 Nobel Prize in physiology or medicine went to three scientists for their work on HIF’s mechanisms, and inhibitors of H1F1A are being developed to treat cancer. They include Seattle Genetics’ PX-478 and Merck & Co.’s MK-6482, a HIF-2α inhibitor developed by Peloton Therapeutics that recently showed promise in a phase 2 study in kidney cancer.
The Sanford Burnham Prebys team believes targeting PPP1R1B could be a new treatment strategy for pancreatic cancer. “With this proof-of-concept data, we can start drug screens that identify an inhibitor of PPP1R1B, which, if successful, may help more people survive pancreatic cancer,” said Anindya Bagchi, the study’s corresponding author, in a statement.