Researchers at Mass General Brigham, led by Yang Zhang, PhD, and Jinjun Shi, PhD, from the Center for Nanomedicine and the Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women’s Hospital, have unveiled groundbreaking findings in the fight against advanced prostate cancer (PCa). Published in ACS Nanoscience Au, their study explores a novel RNA-based therapeutic approach that could restore the balance between cellular growth and inhibition, a crucial factor in tumor suppression.

Prostate cancer, like many other cancers, arises from an imbalance in the body’s ability to regulate cellular growth, resulting in uncontrolled cell proliferation and tumor formation. This process is often driven by the malfunction of specific proteins, including the phosphatase and tensin homologue (PTEN), a tumor suppressor, and the androgen receptor (AR), a pro-tumorigenic transcription factor. Despite extensive research, no existing treatments simultaneously target both the restoration of tumor suppression and the inhibition of growth drivers.

In their study, Zhang and Shi aimed to address this challenge by using a combination of mRNA and small interfering RNA (siRNA) to tackle the dual problem of tumor suppression and excessive growth. They hypothesized that while mRNA could be used to restore the lost PTEN function, siRNA could simultaneously silence the overactive AR signaling pathway, a key contributor to the progression of prostate cancer.

“We hypothesized that using mRNA and siRNA simultaneously could restore tumor suppressors and inhibit drivers of tumor growth, such as PTEN and AR respectively, in patients with PCa,” Zhang explained.

To deliver these therapeutic molecules effectively, the team employed lipid nanoparticles, a delivery system designed to transport the fragile RNA molecules directly to human prostate cancer cells. This method, which has been a focus of recent advancements in RNA-based therapies, ensures that the mRNA and siRNA can be introduced into the target cells without being degraded or rendered ineffective.

The results of this preclinical study were striking. When PCa cells were treated with the lipid nanoparticle-delivered mRNA and siRNA combination, researchers observed a powerful anti-tumor effect. The approach successfully restored PTEN expression, which helped suppress tumor growth, while simultaneously silencing AR activity, preventing further tumor progression.

“The combined effect was potent and offered an anti-tumor response that we had hoped to achieve,” said Shi. “This research shows that our strategy can simultaneously target multiple pathways that drive prostate cancer and potentially other types of cancer.”

While the study’s focus was on prostate cancer, the implications of this approach are far-reaching. The combined RNA therapy could have broader applications for other cancers, such as breast cancer, non-small cell lung cancer, and hepatocellular carcinoma, where similar tumor growth mechanisms and regulatory pathways are at play.

“Our strategy could also apply to other drivers of tumor growth and tumor suppressors in prostate cancer and other types of cancer,” Zhang noted. “By selecting specific pathways to target, this approach could be refined to develop more effective treatments for various cancers.”

This research signals a major step forward in the development of personalized and more effective cancer therapies, moving beyond one-size-fits-all treatments and toward approaches that target the underlying genetic and molecular mechanisms of each cancer type.

While the results in preclinical models are promising, Zhang and Shi are not stopping here. The next phase of their work will expand this approach to assess its effectiveness in a wider range of cancers. Furthermore, the team plans to explore the biological mechanisms behind the combined mRNA and siRNA therapy, which could reveal new targets for therapeutic intervention.

“Understanding the underlying biological mechanisms that led to such powerful anti-tumor effects is critical,” said Shi. “This could open up new therapeutic targets, potentially leading to breakthroughs in the treatment of prostate cancer and other malignancies.”

Zhang and Shi’s work is a crucial piece of the growing body of research focused on RNA-based therapies, particularly in the realm of cancer treatment. With the rapid progress made in RNA technology, the potential for groundbreaking cancer therapies is more real than ever. However, challenges remain, including ensuring the safety and effectiveness of these therapies in human clinical trials, as well as navigating the complexities of individualized cancer care.

In the case of prostate cancer, where effective treatment options have been limited, the hope for new, more targeted therapies has never been more promising. The research from Mass General Brigham represents an important milestone, one that could pave the way for future breakthroughs in cancer care and potentially save countless lives.

For now, the scientific community eagerly awaits the next steps in this exciting journey, which could bring these cutting-edge therapies one step closer to patients who need them most.