Duke Pathology has been awarded a five-year, $3,001,036 Program Project Grant from the National Cancer Institute (NCI) to investigate new treatment approaches for neuroendocrine prostate cancer (NEPC), a rare but highly aggressive form of prostate cancer. The project, led by principal investigator and Associate Professor of Pathology Everardo Macias, PhD, brings together a multidisciplinary team of collaborators, including Department Chair of Pathology Jiaoti Huang, MD, PhD; Andrew Armstrong, MD, MSc, a medical oncologist in the Duke Department of Medicine, Division of Medical Oncology; Zachary Hartman, PhD, director, Center for Applied Therapeutics, associate professor, Departments of Surgery, Pathology, and Integrative Immunobiology; and external partner Sungyong You, PhD, professor and director of the Urologic Oncology Bioinformatics Group at Cedars-Sinai. Umar Mehraj, PhD, a postdoctoral fellow studying under the guidance of Macias, also contributed to the award application.
NEPC is an aggressive, lethal subtype of prostate cancer. While some cases arise independently, it more often develops as a resistance mechanism in castrate resistance prostate cancer (CRPC) patients receiving standard hormone-blocking therapies. These tumors are fast-growing, frequently spread to other parts of the body, and are associated with a poor prognosis—fewer than 20% of patients survive five years after diagnosis. With limited treatment options currently available, there is an urgent need to identify new biological targets that can be leveraged for more effective NEPC therapies.
TTK: A High-Value Target for Therapy
The research team’s project, titled “Defining the Role of TTK in Neuroendocrine Prostate Cancer,” focuses on a protein called Tyrosine Threonine Kinase (TTK), also known as Monopolar Spindle 1 Mps1, which plays a critical role in cell division. In healthy cells, TTK helps ensure that chromosomes are accurately distributed when cells divide. This process is known as the spindle assembly checkpoint (SAC). However, in cancer cells, particularly in NEPC, TTK is produced at abnormally high levels. Notably, TTK is expressed at low levels in normal tissues but becomes increasingly elevated as prostate cancer progresses, making it an attractive and potentially safer target for therapy.
Building on promising preliminary data, Macias’s research team has shown that blocking TTK—either genetically or using drug compounds—can slow tumor growth in laboratory models and animal studies. Importantly, there are already clinical trials exploring TTK, with several drugs designed to inhibit its kinase activity. This potentially paves the way for rapid translation of these findings to patient care.
The research team proposed to explore TTK in depth through three specific aims:
- Investigate how TTK interacts with and regulates the function of another protein, RABL6, which has emerged as a key downstream target that may drive tumor growth in NEPC.
- Test the effects of targeting TTK across multiple models, including cancer cell lines, patient-derived tumor samples, and advanced mouse models, to better understand how it can be effectively inhibited in living systems.
- Evaluate whether combining TTK inhibitors with current standard chemotherapy treatments enhances their effectiveness.
Advancing Toward Better Treatments and Outcomes
To further understand how therapies impact tumors, Macias’s team will also analyze changes in gene expression (transcriptomics) in response to TTK perturbation and examine how immune cells within the tumor microenvironment respond to treatment. These efforts aim to identify biomarkers that could help guide treatment decisions and predict patient response.
If successful, this work will establish TTK as a high-value therapeutic target and lay the groundwork for new treatment strategies that could improve outcomes for patients facing this aggressive disease.