- A new study has identified a protein that helps drive bladder cancer by triggering the synthesis of cholesterol via mouse and cell models.
- Researchers found that a combination therapy of two drugs disrupts this pathway, helping to suppress the creation of cancer cells and tumor growth.
- This combo of medications includes a statin already used for lowering cholesterol and treating cardiovascular disease in humans.
In 2022, more than 600,000 people around the world were diagnosed with bladder cancer, and more than 220,000 people globally died from the disease.
“In 2024, bladder cancer was the
“While there are new treatments for bladder cancer, including immune checkpoint therapy, they are not totally effective, and chemotherapy, radiation, and BCG (Bacillus Calmette-Guerin) remain the most commonly used treatments,” Hunter continued. “Clearly, there is an unmet need for new therapeutic approaches for bladder cancer.”
Hunter is the senior author of a new study recently published in the journal Cancer Discovery that has identified a protein they believe helps drive bladder cancer by triggering the synthesis of cholesterol via both mouse and bladder cancer cell models.
Researchers also found that a combination therapy of two drugs — including a statin already used for lowering cholesterol in humans — disrupts this pathway, suppressing the creation of cancer cells and tumor growth.
For this study, Hunter and his team focused on the protein PIN1, which has been shown to impact the initiation and progress of cancer in previous studies.
“PIN1 is an enzyme that is able to alter the local structure of a protein either increasing or decreasing its activity, but only if a phosphate has been attached to that protein in a particular place first, which is then recognized by PIN1,” Hunter explained. “PIN1 is present in all organisms whose cells have nuclei, from yeast to humans, and its high degree of conservation during evolution indicates it has an important function.”
PIN1 and cancer“In human cells, PIN1 is known to act on many target proteins, tweaking their structures once the phosphate signal has been added by a kinase enzyme. PIN1 is present at high levels in many cancers, such as breast cancer, and has been found to activate proteins in multiple intracellular pathways that drive cancer or inactivate proteins in pathways that normally block excessive growth.”
— Tony Hunter, PhD
“In bladder cancer, our work shows that PIN1 is important for bladder cancer cells to proliferate and grow, and to prevent the tumor cells from committing suicide by a process known as apoptosis,” Hunter added. “PIN1 is also needed for the tumor cells to migrate and invade the surrounding tissue to form a tumor.”
Using both animal and bladder cell models, researchers determined that PIN1 helped direct bladder cancer by triggering the synthesis of cholesterol.
“The cholesterol we mention is the same chemical as the cholesterol that we get through our diet, and also the cholesterol that is made in the liver and enters our circulation,” Hunter said. “Cholesterol is a key building block of cell membranes and is essential for cell viability. All cells in the body can make cholesterol for their own use when the local levels of cholesterol are low, and this is the process that PIN1 is driving in the bladder cancer cells.”
With a new potential drug target for bladder cancer therapy identified, the scientists found that a combination of the statin
Statin + PIN1 inhibitor“Statins block the synthesis of cholesterol in (the) liver to lower the level of circulating cholesterol, which is what is measured when you have a blood draw for a cholesterol test. So simvastatin is acting in the mouse to block both cholesterol made by the cancer cells themselves and by the liver, and sulfopin is working in the tumor cells to decrease synthesis of cholesterol. Together, the combination results in much lower levels of cholesterol in the bladder cancer tissue, thus reducing tumor growth.”
— Tony Hunter, PhD
Given that PIN1 levels are high in several other cancers, Hunter said it is certainly possible that PIN1 may be driving cholesterol production in other types of cancer.
“Therefore, a PIN1 inhibitor drug given in combination with a statin to reduce cholesterol production in the tumor cells and decrease circulating cholesterol produced by the liver might be a viable treatment option in some other cases,” he continued.
“We plan to follow up on our findings to study the roles of PIN1 in other cell types in bladder cancer such as
MNT had the opportunity to speak with Jennifer Linehan, MD, a board certified urologist and associate professor of urology and urologic oncology at Providence Saint John’s Cancer Institute in Santa Monica, CA, about this study, which she said she found interesting and hopeful.
“There is so much about why cancer grows, how cancer forms, that we clearly don’t understand. There [are] definitely actors at play that are dictating the growth, dictating the invasiveness, that we don’t understand. And so I think this is just one of (the tips) of the iceberg,” Linehan told MNT.
Linehan said it is important for researchers to continue to find new ways of treating bladder cancer due to the large surgery required to treat invasive cancer, and it is one of the more expensive cancers to treat because it tends to be so recurrent.
The challenge of treating bladder cancer“Ultimately, especially with invasive bladder cancer, the treatment is removing the bladder which is an incredibly big surgery — it is life changing, it is physiologically changing for your body. If it’s not invasive and it’s recurrent and it keeps coming back, that’s a lot of toll on the patient themselves, as well as it’s also very costly. The patient keeps having to come back for checks, keeps having to have different treatments to keep the cancer at bay.”
— Jennifer Linehan, MD
“Anything that could be curative or stunt (tumor) growth, or we can manipulate (tumor) growth, is very interesting because a lot of the treatments that we have now are to kill what you have,” Linehan continued.
“Some of it is enhancing the body’s own immune system, like immunotherapy … There’s nothing really out there that we’re using that’s going to stop the growth, and so I think that that’s why this is so interesting because that kind of mechanism of treatment is one, not commonly discovered, and two, not commonly pursued,” she added.
