Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in use of AR antagonists and anti-androgen therapies that reduce endogenous steroid hormone production. However, within two to three years of receiving first line androgen deprivation therapy, the majority of patients diagnosed with PCa progress to castration resistant prostate cancer (CRPC). There is an urgent need for therapies that are more durable than antagonism of the AR axis. Studies of Runt-related transcription factors (RUNX) and their heterodimerization partner, Core-Binding Factor Subunit b (CBFβ), are revealing that the RUNX family are drivers of CRPC. In this review, we describe what is presently understood about RUNX members in PCa, including what regulates and is regulated by RUNX proteins, and the role of RUNX proteins in the tumor microenvironment and AR signaling. We discuss the implications for therapeutically targeting RUNX, the potential for RUNX as PCa biomarkers, and the current pressing questions in the field.
One of the learning outcomes of any undergraduate biochemistry course should be an appreciation of the relationship between structure and function in biological macromolecules. The availability of state-of-the-art modeling software provides an opportunity to achieve this goal in interesting ways. The Protein Structure and Function Exploration (PSAFE) project was developed at the University of Virginia to introduce undergraduate biochemists to the significance of structure–function relationships and the nuances of scientific writing. The PSAFE project uses the molecular-document capability of the ICM Browser (from Molsoft LLC) to accomplish its goals. Students in introductory biochemistry lecture courses are each assigned a particular protein or nucleic acid to study and characterize throughout the semester. The students progress from learning the basics of protein structure early in the course to a thorough analysis of their proteins and how they achieve their functions, culminating in production of a descriptive narrative by the end of the semester. The student projects are reviewed and edited and then uploaded to an archival website. More than 1100 such projects have now been archived on this site. The majority of the students in these courses report that the PSAFE project was a challenging but highly satisfying experience that greatly enriched their understanding and appreciation of protein structure. PSAFE Online is now available to any interested instructors and students.
Prostate cancer remains the most diagnosed cancer among men in the United States behind skin cancer, and advanced prostate cancer is the third leading cause of cancer-related deaths, with a 5-year survival rate of 26%. Radiation is the standard of care for the treatment of prostate cancer at the early and late stages. Checkpoint kinase 2 (CHK2) is a serine/threonine protein kinase whose main function is regulating the DNA damage response (DDR) induced by ionizing radiation. The androgen receptor (AR) is a major driver of prostate cancer, even at the castration-resistant stage of the disease. The development of the second-generation anti-androgen enzalutamide, which is a selective AR antagonist, highlights the enduring importance of the AR. We have previously demonstrated that CHK2 is a critical negative regulator of prostate cancer cell growth, androgen sensitivity, and AR transcriptional activity. We have now uncovered novel molecular interactions between CHK2 and AR that provide mechanistic insight into our observation that CHK2 regulates prostate cancer growth. The AR directly interacts with CHK2, and that interaction increases with radiation. We found that the interaction of CHK2 and AR occurs at sites of DNA damage. The binding of CHK2 with AR can be disrupted with CHK2 kinase inhibitors suggesting that the kinase activity of CHK2 is required. This was verified using kinase-impaired CHK2 variants, including the K373E variant associated with 4.2% of prostate cancer. Furthermore, the radiation-induced increase in CHK2-AR interactions requires AR phosphorylation on both serine 81 and serine 308. Interestingly, CHK2-depletion in LNCaP cells increases ionizing radiation induced AR expression and DNA damage. Together, these data provide the rationale for targeting the CHK2-AR signaling axis to improve the effectiveness of prostate cancer therapies. The combination of CHK2 or CDK1 inhibitors with androgen deprivation therapy (ADT) and radiation shows an additive effect on the repression of tumor cell growth. Nearly every patient with disseminated prostate cancer will relapse following ADT and develop incurable castration-resistant prostate cancer. We have uncovered the molecular details of a signaling axis involving CHK2 and AR that, when perturbed in combination with ADT and/or ionizing radiation, effectively inhibits prostate cancer cell growth. This may enable resensitization of castration-resistant prostate cancer to the currently approved treatment options. Citation Format: Huy Q. Ta, Natalia Dworak, Rosalie Sleppy, Jeffery A. Allende, Daniel Gioeli. Translating the functional interactions of checkpoint kinase 2 and the androgen receptor into more effective therapies for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3747.
BackgroundCare management programs are widely used to improve care coordination and management of chronic conditions for high‐need older adults. With many care management programs targeting a small number of people, high‐need older adults may receive services from more than one care management program (co‐occurring care management), the implications of which are unknown.MethodsWe conducted semi‐structured interviews with 37 care managers, 15 older adults, and 13 caregivers, who were recruited through an urban academic medical center and a large rural health system in Maryland. We analyzed interview transcripts using qualitative content analysis with the aim of understanding contributors to, implications of, and strategies to manage co‐occurring care management among high‐need older adults.ResultsContributors to co‐occurring care management included siloed programs due to program‐specific financial incentives and inability to easily identify other involved care managers, and the complex needs of the enrolled older adult population, which motivated involvement of more than one program. Implications of co‐occurring care management included older adults and caregivers feeling cared for and safe when they had multiple care management programs involved and reporting value in their relationships with care managers. Older adults were identified as having greater access to resources and improved care when care manager roles were aligned in a complementary way; however, misaligned roles posed the potential for confusion about care manager accountability for tasks and resulted in frustration and lack of follow‐through. Strategies for managing co‐occurring care management included alignment of care manager roles through communication and negotiation and older adults and caregivers identifying and relying on a single care manager with whom they had the strongest relationship.ConclusionsInitiatives that clarify strengthen the relationship between care managers and older adults, increase care manager visibility, and facilitate communication across care managers may help foster collaboration.
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