Rationale: While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years that is unresponsive to this therapy. Although the hormone-refractory disease is unaffected by androgen deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, the processes downstream of the receptor remain viable targets for therapeutic intervention.

We recently identified one such AR-regulated signaling pathway involving the enzymes Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) and AMP-activated protein kinase (AMPK) that is necessary for prostate cancer cell migration and invasion. Later work by a second independent group confirmed our initial findings and also presented data that suggest this enzymatic cascade promotes the use of sugars as a source for cellular energy, a common trait for rapidly growing cancers. Now we have generated additional evidence that implies that prostate cancers use this same signaling pathway to not only utilize sugars, but also fats to increase cancer cell growth. This means that prostate cancer cells could differ in their metabolism from not only normal cells, but also other types of cancers. As such, classical metabolic-based cancer diagnostics and treatments might not be as applicable to prostate cancers, indicating the development of new approaches is warranted. Collectively, this work indicates that the AR-CaMKKbeta-AMPK signaling pathway increases the progression of prostate cancer by multiple mechanisms, regulating tumor cell migration, invasion, growth, and metabolism.

Objective: The goal of this study is to define the specific role(s) of the CaMKKbeta-AMPK signaling axis in prostate cancer. We hypothesize that the CaMKKbeta-AMPK axis plays a central role in AR pathological signaling and therefore may be exploited to develop both new diagnostic cancer markers and mechanistically novel therapeutics. To test our hypothesis, we will use a combination of approaches to study the impact of this signaling pathway on the metabolism of prostate cancer cells in both isolated and native tumor environment contexts. Further, in human clinical samples, we will evaluate whether elevated CaMKKbeta levels and/or AMPK activity can function as biomarkers for detecting the aggressive stage of the disease. Finally, this project will determine whether the CaMKKbeta-AMPK signaling axis is a viable therapeutic target in preclinical mouse models of advanced prostate cancer.

Applicability: Ultimately, the research described here will help all men at risk of developing prostate cancer because it would: (1) help determine if someone could have an aggressive form of the disease and therefore needs to undergo immediate further treatment and (2) offer a mechanistically new treatment option for men with the hormone-refractory disease. We anticipate the results of this project will immediately establish CaMKKbeta's and AMPK's potential as biomarkers and aid their validation as therapeutic targets. As target validation represents one of the major bottlenecks in drug discovery, this work will provide the proof of principle needed to justify new discovery efforts that in the future could lead to the next major prostate cancer therapeutic.

Contributions to the Field: In addition to the more direct above-mentioned benefits, these studies will fundamentally advance the fields of signal transduction and prostate cancer biology. This advancement will occur because these studies will help determine how elevated AR activity, present in almost all prostate cancers, regulates tumor cell metabolism, an important yet largely unknown area of prostate cancer. By improving our understanding of this area, we establish the possibility of creating a new generation of metabolic-based predictive/diagnostic signatures and therapies.