A hidden link that drives deadly pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadliest type of pancreatic cancer. Most treatment strategies focus on blocking the frequently mutated cancer gene known as KRAS. While this approach can work in some cases, many PDAC tumors ultimately evade these treatments. The researchers believe that combining therapies that hit additional molecular targets could one day help doctors overcome this resistance.
In 2023, Cold Spring Harbor Laboratory (CSHL) researchers Professor Adrian Kreiner identified a protein called SRSF1 as an early driver of PDAC tumor formation. By taking a deeper look at the data from that study, a new team led by Alexander Kral, a former graduate student at CSHL, discovered that SRSF1 does not act on its own. Instead, it acts as part of a three-part molecular system that drives cancer to become more aggressive.
“Our theory was that some changes caused by increased SRSF1 levels were playing a role in the accelerated tumor growth we saw,” Krall explains. “We focused on a molecule that we thought could be an important driver of this called Aurora kinase A (AURKA). We found that it is part of a complex regulatory circuit that includes not only AURKA and SRSF1, but another key cancer gene called MYC.”
How does cancer’s self-reinforcing cycle work?
Within this system, SRSF1 controls AURKA by changing how its genetic instructions are processed through a mechanism known as alternative splicing. This results in higher levels of AURKA, which then helps stabilize and protect the MYC protein. MYC in turn promotes SRSF1 production, setting the whole process in motion again and allowing the cancer-promoting loop to continue.
“Bits and pieces of this circuit were previously known, but we didn’t have the full picture yet,” Kreiner says. “Once we discovered the existence of alternative splicing of AURKA, we could start looking for ways to disable it.”
Circle collapse with one goal
To interfere with this process, the team created an antisense oligonucleotide (ASO) designed to change how AURKA binds. ASOs are short synthetic molecules that the Kreiner laboratory has extensive experience developing. The group previously created Spinraza, the first FDA-approved treatment for spinal muscular atrophy.
Based on their previous findings, the researchers expected that the new ASO would block AURKA binding. Instead, the effect was more dramatic in pancreatic cancer cells. The treatment caused the entire cancer driving circuit to collapse. Cancer cells lost their vitality and activated apoptosis, a form of programmed cell death.
“It’s like killing three birds with one stone,” Kreiner explains. “SRSF1, AURKA, and MYC are all oncogenes that contribute to the development of PDAC. Only by targeting the binding of AURKA to our ASO do we see loss of these two other molecules as well.”
Looking towards future cancer treatments
Kreiner’s lab continues to improve ASO, although any potential use in patients is still far in the future. Kreiner emphasizes that major medical advances often begin with this kind of foundational research. Spinraza followed a similar path before going on to save thousands of lives. With further improvement, this work could one day contribute to a new, effective treatment for pancreatic cancer.
Post Comment