Researchers circumvent a key mechanism in castration-resistant prostate cancer

Researchers circumvent a key mechanism in castration-resistant prostate cancer

Researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown they can bypass a key mechanism in castration-resistant prostate cancer (CRPC), potentially making immunotherapies more effective. By infusing nitric oxide (NO) into animal models, the team shrank tumors and paved the way for possible combination therapies. The study was published in Nature Cell Death & Disease.

We have shown that by treating these animals with exogenous nitric oxide, we reduce oxidative stress, sensitize tumors to therapy that blocks the CSF1 receptor, and rebalance immune components in the tumor microenvironment. This allows us to reduce the burden of these highly resistant tumors.”

Himanshu Arora, Ph.D., assistant professor at Sylvester and Desai Sethi Urology Institute

Many prostate tumors initially respond to antihormone therapies, but can develop resistance over time. Researchers have sought therapeutic alternatives, including immunotherapies, but with mixed results. One potential target is the CSF1 receptor, which plays an important role in the selection of macrophages that 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 re-regulate CSF1, creating more M2 cells and helping the tumor microenvironment to grow and thrive."

Identify why CDF1 inhibition may fail

Scientists have tried to block CSF1 and regain control of tumors, but this approach has so far been unsuccessful, suggesting something else is at play.

In the study, the team identified a number of reasons why CSF1 inhibition may fail. One problem was increased oxidative stress in the tumor microenvironment, which counteracts CSF1 inhibition by disrupting the cellular balance between oxidizing molecules and antioxidants.

More importantly, the researchers showed that an enzyme called nitric oxide synthase 3 (NOS3) loses its function, stops producing NO, and creates a chain of events. Without NO, the CSF1 receptor cannot be nitrosylated, a protein modification that critically influences its function. As a result, the non-nitrosylated protein is unable to properly regulate the balance between M1 and M2 macrophages, strengthening the cancer microenvironment and helping tumors resist CSF1 inhibition.

The team found that by infusing NO, they could reduce oxidative stress and support CSF1 nitrosylation, thereby improving CSF1 inhibition and shrinking prostate tumors.

“This paper is a big deal because it helps us understand this important pathway and has clear implications for treatment,” said Joshua Hare, MD, chief scientific officer of the Miller School and professor of molecular and cellular pharmacology. “The approval of nitrosylation in this protein has a dramatic impact on treatment in this prostate cancer model and is extremely exciting.”

Additional research

This work is just a beginning for Dr. Arora. He also works with Associate Professor Fangliang Zhang, Ph.D. together to understand how nitrosylation and another protein modification, called arginylation, influence immune resistance in high-grade prostate cancer. Additionally, the Arora lab is studying how these mechanisms may influence the effectiveness 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.”

Study partners included clinical researchers Ranjith Ramasamy, MD, Thomas A. Masterson, MD, and Sanoj Punnen, MD; postdoctoral researchers Fakiha Firdaus, Rehana Qureshi and Raul Dulce; and medical students and interns Manish Kuchakulla, MD, Yash Soni and Khushi Shah.

“This article is the result of hard work and persistent contributions from the entire team,” said Dr. Arora. “We are deeply grateful for the continued support we have received from Sylvester, the Desai Sethi Urology Institute and the American Cancer Society, which has enabled us to conduct this comprehensive research.”

Source:

University of Miami Health System, Miller School of Medicine

Reference:

Firdaus, F., et al. (2022) S-nitrosylation of the CSF1 receptor increases the effectiveness of CSF1R blockade against prostate cancer. Cell death and disease. doi.org/10.1038/s41419-022-05289-4.

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