Associate Professor of Pathology Everardo Macias, PhD, has been awarded a highly competitive V Foundation Translational Research Grant to support innovative work aimed at developing new treatment strategies for aggressive, treatment‑resistant prostate cancer. The four‑year award totals $800,000.
Macias will lead the project, titled “Evaluating the Therapeutic Potential and Mechanisms of NUAK2 in Neuroendocrine Prostate Cancer,” in collaboration with Andrew Armstrong, MD, MSc, a medical oncologist in the Duke Department of Medicine, Division of Medical Oncology. Umar Mehraj, PhD, a postdoctoral associate studying under the guidance of Macias, made significant contributions to the award application.
Addressing a Critical Unmet Need
Prostate cancer (PC) is often very treatable when caught early, yet more than 35,000 men in the United States died from advanced disease in 2025. While standard therapies for advanced prostate cancer initially target androgen signaling, tumors frequently evolve over time, becoming resistant to these treatments.
One of the most dangerous forms of treatment-resistant disease is neuroendocrine prostate cancer (NEPC). In this form, cancer cells “reprogram” themselves to grow without relying on androgens. The tumors no longer depend on hormone signaling, rendering many standard PC drugs ineffective.
“Today, patients with NEPC are treated with chemotherapy, but responses are short-lived and no effective long-term therapies exist,” said Macias. “There is an urgent need for new, more effective therapies for patients with NEPC.”
Targeting a Promising New Driver of Disease
Macias and his team have identified a promising new target called NUvel (nua) AmP-activated protein kinase (AMPK)-related kinase 2 (NUAK2), an adenosine monophosphate-activated protein kinase (AMPK)‑family kinase that is a key driver of neuroendocrine prostate cancer.
Although relatively understudied, NUAK2 appears to play an important role in cancer progression. The team’s research shows that high levels of NUAK2 are associated with more aggressive disease and help drive tumor growth by regulating an essential process called RNA splicing that controls how cells regulate mRNA splicing of genes that are then translated to proteins essential for tumor growth.
In preclinical studies, the researchers demonstrated that:
- Blocking NUAK2 either genetically or with drug-based approaches can slow tumor growth
- An FDA‑approved drug, trilaciclib, can be repurposed to inhibit NUAK2 activity, slowing NEPC growth
- Combining this drug with chemotherapy can boost tumor control
Discovering New Therapeutic Options
Building on these findings, the newly funded project will evaluate lerociclib, a next‑generation compound related to trilaciclib that is more potent and better suited for clinical use. The team will also further define how NUAK2 contributes to tumor reprogramming and treatment resistance.
The work will be conducted in advanced preclinical models designed to closely mirror the biology of human NEPC. If successful, this research could lay the groundwork for new treatment strategies that move toward clinical testing, offering hope to patients with few effective options today.
A Translational Approach Focused on Patients
The V Foundation Translational Grant supports research with strong potential to move discoveries from the laboratory into real-world clinical applications. The work of Macias and his team reflects this mission by focusing on therapies with the potential to benefit patients in the near future.
“This work represents an important step toward identifying new targeted therapies for an especially aggressive form of prostate cancer,” said Macias. “Our goal is to translate these findings into meaningful advances that improve outcomes for patients.”
Through this research, Duke Pathology continues to advance discoveries that deepen understanding of cancer biology while moving promising new therapies closer to the clinic.
Their paper is under revision and a bio-archived preprint covers the study in depth: NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer - PMC
The V Foundation for Cancer Research was founded in 1993 by ESPN and the late Jim Valvano, legendary North Carolina State University basketball coach, ESPN commentator and member of the Naismith Memorial Basketball Hall of Fame. The V Foundation has funded over $458 million in game-changing cancer research grants in North America through a competitive process strictly supervised by a Scientific Advisory Committee.