SMART COVID Navigator, a Clinical Decision Support Tool for COVID-19 Treatment: Design and Development Study.

BACKGROUND: COVID-19 caused by SARS-CoV-2 has infected 219 million individuals at the time of writing of this paper. A large volume of research findings from observational studies about disease interactions with COVID-19 is being produced almost daily, making it difficult for physicians to keep track of the latest information on COVID-19's effect on patients with certain pre-existing conditions. OBJECTIVE: In this paper, we describe the creation of a clinical decision support tool, the SMART COVID Navigator, a web application to assist clinicians in treating patients with COVID-19. Our application allows clinicians to access a patient's electronic health records and identify disease interactions from a large set of observational research studies that affect the severity and fatality due to COVID-19. METHODS: The SMART COVID Navigator takes a 2-pronged approach to clinical decision support. The first part is a connection to electronic health record servers, allowing the application to access a patient's medical conditions. The second is accessing data sets with information from various observational studies to determine the latest research findings about COVID-19 outcomes for patients with certain medical conditions. By connecting these 2 data sources, users can see how a patient's medical history will affect their COVID-19 outcomes. RESULTS: The SMART COVID Navigator aggregates patient health information from multiple Fast Healthcare Interoperability Resources-enabled electronic health record systems. This allows physicians to see a comprehensive view of patient health records. The application accesses 2 data sets of over 1100 research studies to provide information on the fatality and severity of COVID-19 for several pre-existing conditions. We also analyzed the results of the collected studies to determine which medical conditions result in an increased chance of severity and fatality of COVID-19 progression. We found that certain conditions result in a higher likelihood of severity and fatality probabilities. We also analyze various cancer tissues and find that the probabilities for fatality vary greatly depending on the tissue being examined. CONCLUSIONS: The SMART COVID Navigator allows physicians to predict the fatality and severity of COVID-19 progression given a particular patient's medical conditions. This can allow physicians to determine how aggressively to treat patients infected with COVID-19 and to prioritize different patients for treatment considering their prior medical conditions.

Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action.

Pathways for non-manufacturers to drive generic drug repurposing for cancer in the U.S.

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these non-manufacturers find it difficult to obtain regulatory approval in the U.S. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs. This limits the broad clinical adoption of these drugs and patient access. In this paper, we explore the regulatory landscape for repurposing of small molecule generic drugs within the U.S. We describe case studies of repurposed drugs that have been successfully incorporated into clinical treatment guidelines for cancer without regulatory approval. To encourage greater adoption of generic drugs in clinical practice-that is, to encourage the repurposing of these drugs-we examine existing Food and Drug Administration (FDA) pathways for approval of new uses or indications for generic drugs. We show how non-manufacturers, who are generally more active in generic drug repurposing than manufacturers, could utilize existing regulatory authorities and pathways, and we describe the challenges they face. We propose an extension of the existing 505(b)(2) new drug application (NDA) approval pathway, called a "labeling-only" 505(b)(2) NDA, that would enable non-manufacturers to seek approval of new indications for well-established small molecule drugs when multiple generic products are already available. It would not require new chemistry, manufacturing, and controls (CMC) data or introducing new drug products into the marketplace. This pathway would unlock innovation broadly and enable patients to benefit from the enormous potential of low-cost generic drugs.

Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers.

Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.