Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Destruction complex dynamics: Wnt/ß-catenin signaling alters Axin-GSK3ß interactions in vivo.

The central regulator of the Wnt/ß-catenin pathway is the Axin/APC/GSK3ß destruction complex (DC), which, under unstimulated conditions, targets cytoplasmic ß-catenin for degradation. How Wnt activation inhibits the DC to permit ß-catenin-dependent signaling remains controversial, in part because the DC and its regulation have never been observed in vivo Using bimolecular fluorescence complementation (BiFC) methods, we have now analyzed the activity of the DC under near-physiological conditions in Drosophila By focusing on well-established patterns of Wnt/Wg signaling in the developing Drosophila wing, we have defined the sequence of events by which activated Wnt receptors induce a conformational change within the DC, resulting in modified Axin-GSK3ß interactions that prevent ß-catenin degradation. Surprisingly, the nucleus is surrounded by active DCs, which principally control the degradation of ß-catenin and thereby nuclear access. These DCs are inactivated and removed upon Wnt signal transduction. These results suggest a novel mechanistic model for dynamic Wnt signal transduction in vivo.

Stand and Move at Work.

Cardiovascular disease and diabetes are epidemic in the United States, and efforts to shift this trend have been largely ineffective. The greatest challenge that health care practitioners face is inspiring the lifestyle changes necessary to prevent or reverse these conditions. New evidence suggests that minimal activity, such as simply standing up periodically and moving around can reduce biomarkers of cardiovascular disease and diabetes. Given the challenge and temporary nature of inspiring habitually sedentary individuals to take on intensive exercise routines, this is an exciting prospect. With this new information, the question becomes: "How do we inspire individuals and populations to get up and move?" Dr. Matthew Buman and his group at Arizona State University are addressing this question through researching methods to inspire individuals and groups to stand at move at work. In support of Dr. Buman's work, we have leveraged subject generated postural data gathered by his group to create a pipeline that processes and analyzes the patterns of subject movement with the prompts they received in order to identify the most effective prompt that elicits standing and moving behavior. The pipeline helps researchers in his group visualize their data in an interactive way and to help inform statistical analyses. In future directions, this pipeline structure can be adopted by various aspects of clinical work such as diagnosis, selection of treatment options, monitoring for changes in a patient's conditions over time, evaluating efficacy of different treatment options, and promoting shared decision-making between providers and patients. They can range from novel ways to visualize PGD to help clinicians and patients identify important and actionable trends, to novel computational solutions, to using these data together with the traditional EHR data to provide clinical decision support that may or may not include visual presentations. Importantly, in this challenge, our focus is on integrating PGD with EHR to improve care within the clinical context, rather than on using these data outside of traditional care settings to promote health and wellness.