From clinical specimens to human cancer preclinical models-a journey the NCI-cell line database-25 years later.

The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi-disciplinary team that collaborated to generated large, comprehensively annotated, cell-line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient-donated specimens that have been remarkably valuable for other types of cancer and disease research. A comprehensive analysis conducted by the NCI Center for Research Strategy of the 278 cell lines reported in the original Journal of Cellular Biochemistry Supplement, documents that these cell lines and related products have since been used in more than 14 000 grants, and 33 207 published scientific reports. This has resulted in over 1.2 million citations using at least one cell line. Many publications involve the use of more than one cell line, to understand the value of the resource collectively rather than individually; this method has resulted in 2.9 million citations. In addition, these cell lines have been linked to 422 clinical trials and cited by 4700 patents through publications. For lung cancer alone, the cell lines have been used in the research cited in the development of over 70 National Comprehensive Cancer Network clinical guidelines. Finally, it must be underscored again, that patient altruism enabled the availability of this invaluable research resource.

Publication of trials funded by the National Heart, Lung, and Blood Institute.

BACKGROUND: Rapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized. METHODS: We analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal. RESULTS: As of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan-Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P=0.004) and higher costs of conducting the trial, up to a threshold of approximately $5 million (P<0.001). The 37 trials that focused on clinical events and cost at least $5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative. CONCLUSIONS: Results of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.).

Changes in the National Cancer Institute's R01 workforce: growth, aging, retention, and policy implications.

Scientific progress and discovery of preventions and cures for life-threatening diseases depend on the vitality of the biomedical research workforce. We analyzed the workforce of cancer researchers applying for and receiving R01 awards from the National Cancer Institute (NCI) from fiscal years 1990 to 2016, the last year prior to implementation of the Next Generation Researchers Initiative. Here we report that the NCI R01 Principal Investigator (PI) workforce expanded 1.4-fold and aged over this time frame. We tracked 9 age groups and found that the number of PIs in the 3 oldest groups increased dramatically, in contrast with the younger groups. Sustained increases in the number of funded older PIs stemmed from increases in the number of older PIs submitting applications, rather than higher funding rates for older PIs. The decline in the number of funded younger PIs was driven in part by (a) a marked increase in time from PhD degree to first R01 application and award, as well as (b) a decrease in retention of PIs in the funded R01 workforce beyond their first R01 award. The NCI is using these and other analyses to inform strategies and policies for attracting, supporting, and retaining meritorious early-career researchers.

Toward Independence: Resubmission Rate of Unfunded National Heart, Lung, and Blood Institute R01 Research Grant Applications Among Early Stage Investigators.

PURPOSE: The current, budget-driven low rate of National Institutes of Health (NIH) funding for biomedical research has raised concerns about new investigators' ability to become independent scientists and their willingness to persist in efforts to secure funding. The authors sought to determine resubmission rates for unfunded National Heart, Lung, and Blood Institute (NHLBI) early stage investigator (ESI) independent research grant (R01) applications and to identify resubmission predictors. METHOD: The authors used a retrospective cohort study design and retrieved applications submitted in fiscal years 2010-2012 from NIH electronic research administrative sources. They defined ESI applicants as those who have received no prior R01 (or equivalent) funding and are within 10 years of completion of their terminal research degree or medical residency training. ESI applications at the NHLBI were eligible for special funding consideration if they scored above, but within 10 points of, the payline. The primary outcome was application resubmission after failing to secure funding with the first R01 submission. RESULTS: Over half of the unfunded applications were resubmitted. Some of these were discussed and "percentiled." Among percentiled applications, the only significant predictor of resubmission was the percentile score. Over half (59%) of the ESI R01 grants funded by NHLBI in fiscal years 2010-2012 had percentile scores above but within 10 points of the NHLBI payline, and benefited from the special funding considerations. CONCLUSIONS: The only independent predictor of resubmission of NHLBI ESI R01 grant applications was percentile score; applicant demographics and institutional factors were not predictive of resubmission.

Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.

This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.

Discovery pharmaceutics--challenges and opportunities.

Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemical parameters. The poor biopharmaceutical properties often lead to extended timelines and a higher cost of developing the compounds. To avoid these problems and choose the best compounds from a biopharmaceutical perspective, physicochemical parameters such as solubility, lipophilicity, and stability need to be evaluated as early as possible. Furthermore, the preformulation approaches used to evaluate the compounds for their pharmacokinetic and toxicological properties need to be optimized. This minireview summarizes some of the parameters and approaches that can be used to evaluate compounds in the early stages of drug discovery.