Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown that they can circumvent a key mechanism in castration-resistant prostate cancer (CRPC) and possibly make immunotherapies more effective. By infusing nitric oxide (NO) into animal models, the team shrank tumors and paved the way for potential combination therapies. The study was published in Nature Cell Death & Disease.
We've shown that, by treating these animals with exogenous nitric oxide, we reduce oxidative stress, sensitize tumors to a therapy that blocks the CSF1 receptor, and rebalance the immune components in the tumor microenvironment. By doing this, we can reduce the burden of these highly resistant tumors."
Himanshu Arora, Ph.D., Assistant Professor at Sylvester and the Desai Sethi Urology Institute
Many prostate tumors initially respond to anti-hormone therapies but, over time, can develop resistance. Researchers have been hunting for therapeutic alternatives, including immunotherapies, but with mixed results. One potential target is the CSF1 receptor, which plays a major role in choosing which macrophages populate the tumor microenvironment.
"The CSF1 receptor regulates macrophage polarization," said Dr. Arora. "In this context, M1 macrophages destroy tumor cells while M2 macrophages suppress the immune response. But mutations can reregulate CSF1, creating more M2 cells and helping the tumor microenvironment grow and thrive."
Identifying why CDF1 inhibition may Fail
Scientists have tried to block CSF1 and take control back from tumors, but this approach has thus far fallen short, suggesting that something else is in play.
In the study, the team identified a number of reasons that CSF1 inhibition can fail. One problem was increased oxidative stress in the tumor microenvironment, which counteracts CSF1 inhibition by disturbing the cellular balance between oxidizing molecules and antioxidants.
Even more importantly, the researchers showed that an enzyme called nitric oxidize synthase 3 (NOS3) loses function, no longer producing NO and generating a chain of events. Without NO, the CSF1 receptor cannot be nitrosylated, a protein modification that critically impacts its function. As a result, the unnitrosylated protein fails to properly govern the balance between M1 and M2 macrophages, boosting the cancer microenvironment and helping tumors resist CSF1 inhibition.
The team found that, by infusing NO, they could reduce the oxidative stress and support CSF1 nitrosylation, improving CSF1 inhibition and shrinking prostate tumors.
"This paper is a big deal because it helps us understand this important pathway and has definite treatment implications," said Joshua Hare, M.D., the Miller School's chief science officer and professor of molecular and cellular pharmacology. "Allowing for nitrosylation in this protein has a dramatic effect on treatment in this prostate cancer model and is extremely exciting."
This work is only a start for Dr. Arora. He is also working with associate professor Fangliang Zhang, Ph.D., to understand how nitrosylation and another protein modification, called arginylation, impact immune resistance in high-grade prostate cancers. In addition, the Arora lab is investigating how these mechanisms may influence the efficacy of other immunotherapies, such as PD-L1 checkpoint inhibitors.
"We can combine these immunotherapies with NO to make them more effective," said Dr. Arora. "We hope to begin preliminary, phase 1 clinical trials to test these therapies in combination and hopefully improve patient outcomes."
Partners on the study included clinical researchers Ranjith Ramasamy, M.D., Thomas A. Masterson, M.D., and Sanoj Punnen, M.D.; post-doctoral researchers Fakiha Firdaus, Rehana Qureshi, and Raul Dulce; and medical students and interns Manish Kuchakulla, M.D., Yash Soni, and Khushi Shah.
"This article is the culmination of hard work and persistent input by the entire team," said Dr. Arora. "We are deeply grateful for the continuous support we have received from Sylvester, the Desai Sethi Urology Institute, and the American Cancer Society, which allowed us to conduct this comprehensive research."
Firdaus, F., et al. (2022) S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer. Cell Death & Disease. doi.org/10.1038/s41419-022-05289-4.