Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically used drugs might be useful in treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large prospective cohort study. In stage one, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate, given its potency in inhibiting proliferation in vitro (the concentration of the drug at which proliferation was inhibited by 50%: mean of 163 nM) and its common use. In stage two, we evaluated the association between the leading candidate drug from stage one and prostate cancer risk in 47,884 men followed up from 1986 through 2006. Regular digoxin users [vs nonusers: relative risk (RR) = 0.76; 95% confidence interval (CI), 0.61–0.95], especially users for ≥10 years (RR = 0.54; 95% CI, 0.37–0.79; P trend < 0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro, and its use was associated with a 25% lower prostate cancer risk. Significance: Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing. Cancer Discovery; 1(1); 68–77. ©2011 AACR. Read the Commentary on this article by Spitz et al., p. 21 This article is highlighted in the In This Issue feature, p. 4

Over 1.3 million people live with colorectal cancer in the United States. Physical activity is associated with lower risk of colorectal cancer recurrence and mortality. Interventions are needed to increase physical activity in colorectal cancer survivors. We conducted a 2-arm non-blinded pilot randomized controlled trial at the University of California, San Francisco among 42 individuals who had completed curative-intent treatment for colorectal cancer to determine the feasibility and acceptability of a 12-week (84 days) physical activity intervention using a Fitbit Flex™ and daily text messages. Participants were randomized 1:1 to receive the intervention with print educational materials or print educational materials alone. We explored the impact of the intervention versus usual care on physical activity using ActiGraph GT3X+ accelerometers pre−/post-intervention. We screened 406 individuals and randomized 42 to intervention (n = 21) or control (n = 21) groups. During the 12-week study, the intervention arm wore their Fitbits a median of 74 days [88% of days in study period, interquartile range: 23–83 days] and responded to a median of 34 (out of 46) text messages that asked for a reply (interquartile range: 13–38 text messages). Among the 16 intervention participants who completed the feedback survey, the majority (88%) reported that the intervention motivated them to exercise and that they were satisfied with their experience. No statistically significant difference in change in moderate-to-vigorous physical activity was found from baseline to 12 weeks between arms. A 12-week physical activity intervention with a Fitbit and text messages was feasible and acceptable among colorectal cancer patients after curative treatment. Larger studies are needed to determine whether the intervention increases physical activity. Clinicaltrials.gov Identifier NCT02966054 . Registered 17 November 2016, retrospectively registered.

Background: Altering the systemic milieu through exercise has been proposed as a potential mechanism underlying exercise-driven tumour suppression. It is not yet known whether men with advanced prostate cancer can elicit such adaptations following a program of exercise. The purpose is to examine myokine levels of serum acquired from metastatic castrate-resistant prostate cancer (mCRPC) patients recruited to the INTERVAL-GAP4 trial before and after 6 months of exercise and its tumour-suppressive effect. Methods: Twenty-five men with mCRPC (age = 74.7 ± 7.1 yrs) were randomised to supervised multimodal (aerobic and resistance) exercise (EX) or self-directed exercise control group (CON). Body composition was assessed using dual-energy x-ray absorptiometry (DXA), and fasting blood in a rested state was collected at baseline and at 6 months. Serum levels of myokines (SPARC, OSM, decorin, IGF-1, and IGFBP-3) were measured. Serum was applied to the prostate cancer cell line DU145, and growth was assessed for 72 h. Results: No significant change in body composition was observed. Adjusted serum OSM (P = 0.050) and relative OSM (P = 0.083), serum SPARC (P = 0.022) and relative SPARC (P = 0.025) increased in EX compared to CON. The area under curve (AUC) over 72 h showed a significant reduction in DU145 growth after applying post-intervention serum from the EX vs CON (P = 0.029). Conclusion: Elevated myokine expressions and greater tumour-suppressive effects of serum after 6 months of periodised and autoregulated supervised exercise was observed in men with mCRPC. Exercise-induced systemic changes may slow disease progression in men with advanced prostate cancer.